Substituted pyridine compounds and methods of use

ABSTRACT

Selected novel substituted pyridine compounds are effective for prophylaxis and treatment of diseases, such as TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseases, and other maladies, such as pain and diabetes. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving inflammation, pain, diabetes, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

This application is a division of application Ser. No. 09/642,860, filedAug. 21, 2000, now U.S. Pat. No. 6,333,341, which is a division ofapplication Ser. No. 09/431,410, filed Nov. 1, 1999, now U.S. Pat. No.6,184,237 which is a division of application Ser. No. 09/185,119, filedNov. 3, 1998, now U.S. Pat. No. 6,022,884 which claims the benefit ofProvisional Application Serial No. 60/064,953, filed Nov. 7, 1997, whichare hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention comprises a new class of compounds useful intreating diseases, such as TNF-α, IL-1β, IL-6 and/or IL-8 mediateddiseases and other maladies, such as pain, cancer, and diabetes. Inparticular, the compounds of the invention are useful for theprophylaxis and treatment of diseases or conditions involvinginflammation. This invention also relates to intermediates and processesuseful in the preparation of such compounds.

Interleukin-1 (IL-1) and Tumor Necrosis Factor a (TNF-α) arepro-inflammatory cytokines secreted by a variety of cells, includingmonocytes and macrophages, in response to many inflammatory stimuli(e.g., lipopolysaccharide—LPS) or external cellular stress (e.g.,osmotic shock and peroxide).

Elevated levels of TNF-α and/or IL-1 over basal levels have beenimplicated in mediating or exacerbating a number of disease statesincluding rheumatoid arthritis; Pagets disease; osteophorosis; multiplemyeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic βcell destruction; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscledegeneration; cachexia; Reiter's syndrome; type I and type II diabetes;bone resorption diseases; graft vs. host reaction; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; cerebralmalaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgiasdue to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster are also exacerbated by TNF-α.

It has been reported that TNF-α plays a role in head trauma, stroke, andischemia. For instance, in animal models of head trauma (rat), TNF-αlevels increased in the contused hemisphere (Shohami et al., J. Cereb.Blood Flow Metab. 14, 615 (1994)). In a rat model of ischemia whereinthe middle cerebral artery was occluded, the levels of TNF-α mRNA ofTNF-α increased (Feurstein et al., Neurosci. Lett. 164, 125 (1993)).Administration of TNF-α into the rat cortex has been reported to resultin significant neutrophil accumulation in capillaries and adherence insmall blood vessels. TNF-α promotes the infiltration of other cytokines(IL-1β, IL-6) and also chemokines, which promote neutrophil infiltrationinto the infarct area (Feurstein, Stroke 25, 1481 ). TNF-α has also beenimplicated to play a role in type II diabetes (Endocrinol. 130, 43-52,1992; and Endocrinol. 136, 1474-1481, 1995).

TNF-α appears to play a role in promoting certain viral life cycles anddisease states associated with them. For instance, TNF-α secreted bymonocytes induced elevated levels of HIV expression in a chronicallyinfected T cell clone (Clouse et al., J. Immunol. 142, 431 (1989)).Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discussed the role ofTNF-α in the HIV associated states of cachexia and muscle degradation.

TNF-α is upstream in the cytokine cascade of inflammation. As a result,elevated levels of TNF-α may lead to elevated levels of otherinflammatory and proinflammatory cytokines, such as IL-1, IL-6, andIL-8.

Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type Iand type II diabetes; bone resorption diseases; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; sepsis;septic shock; and toxic shock syndrome. Viruses sensitive to TNF-ainhibition, e.g., HIV-1, HIV-2, HIV-3, are also affected by IL-1.

TNF-α and IL-1 appear to play a role in pancreatic β cell destructionand diabetes. Pancreatic β cells produce insulin which helps mediateblood glucose homeostasis. Deterioration of pancreatic β cells oftenaccompanies type I diabetes. Pancreatic β cell functional abnormalitiesmay occur in patients with type II diabetes. Type II diabetes ischaracterized by a functional resistance to insulin. Further, type IIdiabetes is also often accompanied by elevated levels of plasma glucagonand increased rates of hepatic glucose production. Glucagon is aregulatory hormone that attenuates liver gluconeogenesis inhibition byinsulin. Glucagon receptors have been found in the liver, kidney andadipose tissue. Thus glucagon antagonists are useful for attenuatingplasma glucose levels (WO 97/16442, incorporated herein by reference inits entirety). By antagonizing the glucagon receptors, it is thoughtthat insulin responsiveness in the liver will improve, therebydecreasing gluconeogenesis and lowering the rate of hepatic glucoseproduction.

In rheumatoid arthritis models in animals, multiple intra-articularinjections of IL-1 have led to an acute and destructive form ofarthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382(1990)). In studies using cultured rheumatoid synovial cells, IL-1 is amore potent inducer of stromelysin than is TNF-α (Firestein, Am. J.Pathol. 140, 1309 (1992)). At sites of local injection, neutrophil,lymphocyte, and monocyte emigration has been observed. The emigration isattributed to the induction of chemokines (e.g., IL-8), and theup-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5,517-531 (1994)).

IL-1 also appears to play a role in promoting certain viral life cycles.For example, cytokine-induced increase of HIV expression in achronically infected macrophage line has been associated with aconcomitant and selective increase in IL-1 production (Folks et al., J.Immunol. 136, 4049 (1986)). Beutler et al. (J. Immunol. 135, 3969(1985)) discussed the role of IL-1 in cachexia. Baracos et al. (New Eng.J. Med. 308, 553 (1983)) discussed the role of IL-1 in muscledegeneration.

In rheumatoid arthritis, both IL-1 and TNF-α induce synoviocytes andchondrocytes to produce collagenase and neutral proteases, which leadsto tissue destruction within the arthritic joints. In a model ofarthritis (collagen-induced arthritis (CIA) in rats and mice),intra-articular administration of TNF-α either prior to or after theinduction of CIA led to an accelerated onset of arthritis and a moresevere course of the disease (Brahn et al., Lymphokine Cytokine Res. 11,253 (1992); and Cooper, Clin. Exp. Immunol. 898, 244 (1992)).

IL-8 has been implicated in exacerbating and/or causing many diseasestates in which massive neutrophil infiltration into sites ofinflammation or injury (e.g., ischemia) is mediated by the chemotacticnature of IL-8, including, but not limited to, the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has the ability to activate neutrophils. Thus, reduction inIL-8 levels may lead to diminished neutrophil infiltration.

Several approaches have been taken to block the effect of TNF-α. Oneapproach involves using soluble receptors for TNF-α (e.g., TNFR-55 orTNFR-75), which have demonstrated efficacy in animal models ofTNF-α-mediated disease states. A second approach to neutralizing TNF-αusing a monoclonal antibody specific to TNF-α, cA2, has demonstratedimprovement in swollen joint count in a Phase II human trial ofrheumatoid arthritis (Maini et al., Immunological Reviews, pp. 195-223(1995)). These approaches block the effects of TNF-α and IL-1 by eitherprotein sequestration or receptor antagonism.

The present invention also relates to a method of treating cancer whichis mediated by Raf and Raf-inducable proteins. Raf proteins are kinasesactivated in response to extracellular mitogenic stimuli such as PDGF,EGF, acidic FGF, thrombin, insulin or endothelin, and also in responseto oncoproteins such as v-src, v-sis, and v-fms. Raf functionsdownstream of ras in signal transduction from the cellular membrane tothe nucleus. Compounds in the present invention may be oncolyticsthrough the antagonism of Raf kinase. Antisense constructs which reducecellular levels of c-Raf and hence Raf activity inhibit the growth ofrodent fibroblasts in soft agar, while exhibiting little or no generalcytotoxicity. This inhibition of growth in soft agar is highlypredictive of tumor responsiveness in whole animals. Moreover Rafantisense constructs have shown efficacy in reducing tumor burden inanimals. Examples of cancers where Raf kinase is implicated byoverexpression include cancers of the brain, larynx, lung, lymphaticsystem, urinary tract and stomach, including hystocytic lymphoma, lungadenocarcinoma and small cell lung cancers. Other examples includecancers involving overexpression of upstream activators of Raf orRaf-activating oncogenes, including pancreatic and breast carcinoma.

Substituted imidazole and pyrrole compounds have been described for usein the treatment of cytokine mediated diseases by inhibition ofproinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF. Substitutedimidazoles for use in the treatment of cytokine mediated diseases havebeen described in U.S. Pat. No. 5,593,992; WO 93/14081; WO 96/18626; WO96/21452; WO 96/21654; WO 96/40143; WO 97/05878; WO 97/05878; (each ofwhich is incorporated herein by reference in its entirety). Substitutedimidazoles for use in the treatment of inflammation has been describedin U.S. Pat. No. 3,929,807 (which is incorporated herein by reference inits entirety). Substituted pyrrole compounds for use in the treatment ofcytokine mediated diseases have been described in WO 97/05877; WO97/05878; WO 97/16426; WO 97/16441; and WO 97/16442 (each of which isincorporated herein by reference in its entirety).

Substituted 2-aminopyridine compounds have been described as nitricoxide synthase inhibitors for use in the treatment of inflammation,neurodegenerative disorders and disorders of gastrointestinal motilityin WO 96/18616 and WO 96/18617.

Diaryl substituted pyridine compounds have been described for use in thetreatment of inflammation and inflammation related disorders in WO96/24584 and U.S. Pat. No. 5,596,008.

U.S. Pat. No. 3,980,652, U.S. Pat. No. 3,991,057 and U.S. Pat. No.4,002,629 describe piperazinyl substituted pyridine compounds for use asanti-inflammatory and cardiovascular agents.

JP 6135934 describes substituted pyridine compounds as phospholipase A2inhibitors for use as antiphlogistic and anti-pancreatitis agents. GB1,189,188 describes pyrimidin-2-ylamino substituted pyridine compoundsas therapeutically valuable compounds for use as antiphlogistic agents.

BRIEF DESCRIPTION OF THE INVENTION

The present invention comprises a new class of compounds useful in theprophylaxis and treatment of diseases, such as TNF-α, IL-1β, IL-6 and/orIL-8 mediated diseases and other maladies, such as pain, cancer, anddiabetes. In particular, the compounds of the invention are useful forthe prophylaxis and treatment of diseases or conditions involvinginflammation. Accordingly, the invention also comprises pharmaceuticalcompositions comprising the compounds, methods for the prophylaxis andtreatment of TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseases, such asinflammatory, pain and diabetes diseases, using the compounds andcompositions of the invention, and intermediates and processes usefulfor the preparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

wherein R¹, R⁵, R⁶, R⁷, X and Y are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided compounds ofthe formula:

or a pharmaceutically acceptable salt thereof, wherein

X is O, S, S(O), S(O)₂ or NR²; preferably, X is O, S or NR²; morepreferably, X is O or NR²; most preferably, X is NR²;

Y is —C(O)—NR³R⁴ or —NR⁴—C(O)—R³;

R¹ is a cycloalkyl, aryl, heterocyclyl or heteroaryl radical which isoptionally substituted by 1-4 radicals of alkyl, halo, haloalkyl, cyano,azido, nitro, amidino, R¹⁸—Z¹⁸— or R¹⁸—Z¹⁸-alkyl;

preferably, R¹ is a cycloalkyl, aryl, heterocyclyl or heteroaryl radicalwhich is optionally substituted by 1-4 radicals of C₁-C₆ alkyl, halo,C₁-C₆ haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino,R¹⁸—Z¹⁸— or R¹⁸—Z¹⁸—C₁-C₆ alkyl;

more preferably, R¹ is a cycloalkyl, aryl, heterocyclyl or heteroarylradical which is optionally substituted by 1-4 radicals of C₁-C₄ alkyl,halo, C₁-C₄ haloalkyl of 1-3 halo radicals, cyano, azido, nitro,amidino, R¹⁸—Z¹⁸— or R¹⁸—Z¹⁸—C₁-C₄ alkyl;

provided that the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R¹ is 1-3, preferably, 1-2, and provided when Yis —NR⁴—C(O)—R³ and X is O or S, R¹ is other than a 2-pyrimidinylradical;

more preferably, R¹ is a radical of the formula

wherein R²², R²³, R²⁴, R²⁵ and R²⁶ are each independently a radical ofhydrogen, C₁-C₄ alkyl, halo, trifluoromethyl, cyano, azido, nitro,amidino, R¹⁸—Z¹⁸— or R¹⁸—Z¹⁸—C₁-C₄ alkyl; provided at least one of R²¹,R²², R²³, R²⁴ and R²⁵ is hydrogen; and provided that the combined totalnumber of aryl and heteroaryl radicals in R²², R²³, R²⁴, R²⁵ and R²⁶ is0-1;

R² is a hydrogen or alkyl radical; preferably, R² is a hydrogen or C₁-C₄alkyl radical; more preferably, R² is a hydrogen or C₁-C₂ alkyl radical;more preferably, R² is a hydrogen or methyl radical; and most:preferably, R² is a hydrogen radical;

R³ is an aryl or heteroaryl radical which is optionally substituted by1-5 radicals of alkyl, halo, haloalkyl, cyano, azido, nitro, amidino,R¹⁹—Z¹⁹— or R¹⁹—Z¹⁹-alkyl; preferably, R³ is an aryl or heteroarylradical which is optionally substituted by 1-5 radicals of C₁-C₆ alkyl,halo, C₁-C₆ haloalkyl of 1-3 halo radicals, cyano, azido, nitro,amidino, R¹⁹—Z¹⁹— or R¹⁹—Z¹⁹—C₁-C₆ alkyl; more preferably, R³ is an arylor heteroaryl radical which is optionally substituted by 1-5 radicals ofC₁-C₆ alkyl, halo, C₁-C₄ haloalkyl of 1-3 halo radicals, cyano, azido,nitro, amidino, R¹⁹—Z¹⁹— or R¹⁹—Z¹⁹—C₁-C₄ alkyl;

provided that the total number of aryl and heteroaryl radicals in R³ is1-3, preferably, 1-2; and provided when Y is —C(O)—NR³R⁴, R³ is otherthan a phenyl or naphthyl having an amino, nitro, cyano, carboxy oralkoxycarbonyl substituent bonded to the ring carbon atom adjacent tothe ring carbon atom bonded to —NR⁴—;

more preferably, R³ is a radical of the formula

wherein

U is C—R¹³ or N;

V and W are each independently C—R¹² or N;

R¹¹ and R¹³ are each independently a radical of hydrogen, C₁-C₄ alkyl,halo, trifluoromethyl, cyano, azido, nitro, amidino or R¹⁹—Z¹⁹—;preferably, R¹¹ and R¹³ are each independently a radical of hydrogen,methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, azido, nitro,amidino, R¹⁹—O—, R¹⁹—S(O)₂—, R¹⁹—O—C(O)—, R¹⁹C(O)—, R¹⁹—NR²¹—C(O)— orR¹⁹—NR²¹—S(O)₂—;

each R¹² is independently a radical of hydrogen, C₁-C₆ alkyl, halo,C₁-C₄ haloalkyl of 1-3 halo radicals, R³¹—Z³¹— or R³¹—Z³¹—C₁-C₄ alkyl;preferably, each R¹² is independently a radical of hydrogen, methyl,ethyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy,ethoxy, amino, methylamino, dimethylamino, acetylamino, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, aminomethyl,(methylamino)methyl or (dimethylamino)methyl;

provided that the combined total number of aryl and heteroaryl radicalsin R¹¹, R¹² and R¹³ is 0-1;

wherein each R³¹ is independently a hydrogen, C₁-C₄ alkyl,trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl or heteroaryl-C₁-C₄alkyl radical, wherein the aryl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino,methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl,trifluoromethyl or trifluoromethoxy;

each Z³¹ is independently —O—, —NR²¹—, —NR²¹—C(O)—, —C(O)—NR²¹—,—NR—S(O)₂— or —S(O)₂—NR²¹—;

R⁴ is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl or R²⁰ —Z²⁰-alkyl radical,wherein the aryl and heteroaryl radicals are optionally substituted by1-3 radicals of hydroxy, alkoxy, alkylthiol, amino, alkylamino,dialkylamino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl,alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido,alkyl, haloalkyl or haloalkoxy;

preferably, R⁴ is a radical of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₁-C₆ haloalkyl of 1-3 halo radicals, C₂-C₆ haloalkenyl of 1-3 haloradicals, aryl, heteroaryl, aryl-C₁-C4 alkyl, heteroaryl-C₁-C₄ alkyl orR²⁰—Z²⁰—C₁-C₆ alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-3 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, C₁-C₄ alkylsulfonylamino, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, (C₁-C₄ alkoxy)carbonylamino, (C₁-C₄ alkoxy)carbonyl,cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals orC₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, R⁴ is a radical of hydrogen, C₁-C₆ alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl, heteroaryl-C₁-C₄ alkyl or R²⁰—Z²⁰—C₂-C₄alkyl radical, wherein the aryl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol,amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, acetylamino, halo, C₁-C₄alkyl, trifluoromethyl or trifluoromethoxy;

more preferably, R⁴ is a radical of hydrogen, C₁-C₆ alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl, heteroaryl-C₁-C₄ alkyl or R²⁰—Z²⁰—C₂-C₄alkyl radical, wherein the aryl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol,ethylthiol, amino, methylamino, dimethylamino, ethylamino, diethylamino,acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;

more preferably, R⁴ is a radical of hydrogen, methyl or ethyl radical;

wherein each R¹⁸ is independently a hydrogen, alkyl, haloalkyl, aryl,heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl andheteroaryl radicals are optionally substituted by 1-3 radicals ofhydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino,alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl,alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl,haloalkyl or haloalkoxy;

preferably, each R¹⁸ is independently a hydrogen, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C₁-C₄ alkyl orheteroaryl-C₁-C₄ alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-3 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, C₁-C₄ alkylsulfonylamino, C₁-C₄ alkylsulfonyl, C₁-C₄alkylsulfonyl, (C₁-C₄ alkoxy)carbonylamino, (C₁-C₄ alkoxy)carbonyl,cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals orC₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each R¹⁸ is independently a hydrogen, C₁-C₄ alkyl,trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₂ alkyl or heteroaryl-C₁-C₂alkyl radical, wherein the aryl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol,amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, acetylamino, cyano, halo,azido, C₁-C₄ alkyl, trifluoromethyl or trifluoromethoxy;

each Z¹⁸ is independently —O—, —S—, —S(O)—, —S(O)₂—, —CO₂—, —C(O)—,—NR²¹—, —NR²¹—C(O)—, —C(O)—NR²¹, —NR²¹—S(O)₂— or —S(O)₂—NR²¹—;preferably, each Z¹⁸ is independently —O—, —S—, —S(O)₂—, —CO₂—, —NR²¹—,—NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or —S(O)₂—NR²¹;

wherein each R¹⁹ is independently a hydrogen, alkyl, haloalkyl, aryl,heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl andheteroaryl radicals are optionally substituted by 1-3 radicals ofhydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino,alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl,alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl,haloalkyl or haloalkoxy;

preferably, each R¹⁹ is independently a hydrogen, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C₁-C₄ alkyl orheteroaryl-C₁-C₄ alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-3 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, C₁-C₄ alkylsulfonylamino, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, (C₁-C₄ alkoxy)carbonylamino, (C₁-C₄ alkoxy)carbonyl,cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals orC₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each R¹⁹ is independently a hydrogen, C₁-C₄ alkyl,trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl or heteroaryl-C₁-C₄alkyl radical, wherein the aryl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol,amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, acetylamino, cyano, halo,C₁-C₄ alkyl, trifluoromethyl or trifluoromethoxy;

more preferably, each R¹⁹ is independently a hydrogen, C₁-C₄ alkyl,trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl or heteroaryl-C₁-C₄alkyl radical; wherein the aryl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino,methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl,trifluoromethyl or trifluoromethoxy;

more preferably, each R¹⁹ is independently a hydrogen, methyl, ethyl,trifluoromethyl, phenyl, heteroaryl, phenylmethyl or heteroaryl-methylradical, wherein the phenyl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino,methylamino, dimethylamino, acetylamino, cyano, fluoro, chloro, methyl,ethyl, trifluoromethyl or trifluoromethoxy;

each Z¹⁹ is independently —O—, —S—, —S(O)—, —S(O)₂—, —CO₂—, —C(O)—,—NR²¹—, —NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or —S(O)₂—NR²¹—;preferably, each Z²¹ is independently —O—, —S(O)₂—, —CO₂—, —C(O)—,—NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or —S(O)₂—NR²¹—; more preferably,each Z is independently —O—, —S(O)₂—, —O—C(O)—, —C(O)—, —NR²¹—C(O)— or—NR²¹—S(O)₂—;

wherein each R²⁰ is independently a hydrogen, alkyl, haloalkyl, aryl,heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl andheteroaryl radicals are optionally substituted by 1-3 radicals ofhydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino,alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl,alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl,haloalkyl or haloalkoxy;

preferably, each R²⁰ is independently a hydrogen, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C₁-C₄ alkyl orheteroaryl-C₁-C₄ alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-3 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, C₁-C₄ alkylsulfonylamino, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, (C₁-C₄ alkoxy)carbonylamino, (C₁-C₄ alkoxy)carbonyl,cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals orC₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each R²⁰ is independently a hydrogen, C₁-C₄ alkyl,aryl, heteroaryl, aryl-C₁-C₂ alkyl or heteroaryl-C₁-C₂ alkyl radical,wherein the aryl and heteroaryl radicals are optionally substituted by1-2 radicals of hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol, amino, C₁-C₄alkylamino, di(C₁-C₄ alkyl)amino, acetylamino, halo, C₁-C₄ alkyl,trifluoromethyl or trifluoromethoxy;

more preferably, each R²⁰ is independently a hydrogen, C₁-C₄ alkyl,aryl, heteroaryl, aryl-C₁-C₂ alkyl or heteroaryl-C₁-C₂ alkyl radical,wherein the aryl and heteroaryl radicals are optionally substituted by1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol, ethylthiol,amino, methylamino, dimethylamino, ethylamino, diethylamino,acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;

each Z²⁰ is independently —O—, —S, —S(O)—, —S(O)₂—, —CO₂—, —C(O)—,—NR²¹—, —NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or —S(O)₂—NR²¹—;preferably, each Z²⁰ is independently —O— or —NR²¹—;

wherein each R²¹ is independently a hydrogen or alkyl radical;preferably, each R²¹ is independently a hydrogen or C₁-C₄ alkyl radical;more preferably, each R²¹ is independently a hydrogen or methyl radical;

R⁵ and R⁶ are each independently a hydrogen, alkyl, halo, haloalkyl,haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino,alkylamino, dialkylamino, alkanoylamino, alkylsulfonylamino,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy,hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy,alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical;

preferably, R⁵ and R⁶ are each independently a hydrogen, C₁-C₄ alkyl,halo, C₁-C₄ haloalkyl of 1-3 halo radicals, C₁-C₄ haloalkoxy of 1-3 haloradicals, C₁-C₄ aminoalkyl, (C₁-C₄ alkyl)amino-C₁-C₄ alkyl, di(C₁-C₄alkyl)amino-C₁-C₄ alkyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino,C₁-C₅ alkanoylamino, C₁-C₄ alkylsulfonylamino, aminosulfonyl, C₁-C₄alkylaminosulfonyl, di(C₁-C₄ alkyl)aminosulfonyl, hydroxy, C₁-C₄hydroxyalkyl, thiol, C₁-C₄ alkylthiol, C₁-C₄ alkylsulfonyl, C₁-C₄alkylsulfonyl, C₁-C₄ alkoxy, (C₁-C₄ alkoxy)C₁-C₄ alkyl, cyano, azido,nitro, carboxy, (C₁-C₄ alkoxy)carbonyl, aminocarbonyl, (C₁-C₄alkyl)aminocarbonyl or di(C₁-C₄ alkyl)aminocarbonyl radical;

more preferably, R⁵ and R⁶ are each independently a hydrogen, C₁-C₄alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C₁-C₄ alkylamino,di(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, hydroxy, C₁-C₄ hydroxyalkyl,C₁-C₄ alkoxy, cyano, azido, nitro, carboxy, (C₁-C₄ alkoxy)carbonyl,aminocarbonyl, (C₁-C₄ alkyl) aminocarbonyl or di (C₁-C₄ alkyl)aminocarbonyl radical;

more preferably, R⁵ and R⁶ are each independently a hydrogen, methyl,ethyl, halo, trifluoromethyl, trifluoromethoxy, amino, C₁-C₂ alkylamino,di(C₁-C₂ alkyl)amino, hydroxy, methoxy or ethoxy radical; mostpreferably, R⁵ and R⁶ are each a hydrogen radical;

R⁷ is a hydrogen, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol, alkylthiol,alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano, azido, nitro,carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl radical;

preferably, R⁷ is a hydrogen, C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl of 1-3halo radicals, C₁-C₄ haloalkoxy of 1-3 halo radicals, C₁-C₄ aminoalkyl,(C₁-C₄ alkyl)amino-C₁-C₄ alkyl, di(C₁-C₄ alkyl)amino-C₁-C₄ alkyl,aminosulfonyl, C₁-C₄ alkylaminosulfonyl, di(C₁-C₄ alkyl)aminosulfonyl,hydroxy, C₁-C₄ hydroxyalkyl, thiol, C₁-C₄ alkylthiol, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxy, (C₁-C₄ alkoxy)C₁-C₄alkyl, cyano, azido, nitro, carboxy, (C₁-C₄ alkoxy)carbonyl,aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl or di(C₁-C₄alkyl)aminocarbonyl radical;

more preferably, R⁷ is a hydrogen, C₁-C₄ alkyl, halo, trifluoromethyl,trifluoromethoxy, hydroxy, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, carboxy,(C₁-C₄ alkoxy)carbonyl, aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl ordi(C₁-C₄ alkyl)aminocarbonyl radical;

more preferably, R⁷ is a hydrogen, methyl, ethyl, halo, trifluoromethyl,trifluoromethoxy, hydroxy, methoxy or ethoxy radical; most preferably,R⁷ is a hydrogen radical.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Compounds of interest include the following:

2-cyclohexyloxy-5-(2-chlorophenylcarbonylamino)pyridine;

2-cyclohexyloxy-5-(2-methylphenylcarbonylamino)pyridine;

2-cyclohexyloxy-5-(2,6-dichlorophenylcarbonylamino) pyridine;

2-cyclohexyloxy-5-(2,6-dimethylphenylcarbonylamino) pyridine;

2-(2,4-dimethylphenoxy)-5-(2-chlorophenylcarbonylamino) pyridine;

2-(2,4-dimethylphenoxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;

2-(2,4-dimethylphenoxy)-5-(2-methylphenylcarbonylamino) pyridine;

2-(2,6-dimethyl-4-chlorophenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;

2-(2-methyl-4-fluorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-(2-chlorophenylcarbonyl amino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2-methylphenoxy)-5-(2-chlorophenylcarbonylamino) pyridine;

2-(2-methylphenoxy)-5-(2,6-dichlorophenyl carbonylamino)pyridine;

2-(2-methylphenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-(2,6-dichlorophenylcarbonylamino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-(2,6-dimethylphenylcarbonylamino)pyridine;

2-(4-chlorophenoxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;

2-(2-methyl-4-fluorophenoxy)-5-(2,6-dichlorophenylcarbonylamino)pyridine;

2-(2-methyl-4-fluorophenoxy)-5-(2,6-dimethylphenylcarbonylamino)pyridine;

2-(2-methylphenoxy)-5-(2,6-dimethylphenyl carbonylamino)pyridine;

2-(2-methyl-4-fluorophenoxy)-5-(2-fluorophenylcarbonyl amino)pyridine;

2-(2,4-dimethylphenoxy)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;

2-(1-naphthyloxy)-5-(2-methylphenylcarbonylamino) pyridine;

2-(1-naphthyloxy)-5-(2,6-dichlorophenylcarbonylamino) pyridine;

2-(1-naphthyloxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;

2-(2-methyl-3-pyridyloxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-((3,5-dimethyl-4-isoxazolyl)carbonylamino)pyridine;

2-(2-methyl-4-chlorophenylthiol)-5-(2-methylphenylcarbonylamino)pyridine;

2-(2-methyl-4-chlorophenylthiol)-5-(2,6-dimethylphenylcarbonylamino)pyridine;

2-cyclohexylamino-5-(2,6-dichlorophenylcarbonylamino) pyridine;

2-cyclohexylamino-5-(2,6-dimethylphenylcarbonylamino) pyridine;

2-(2-methylcyclohexylamino)-5-(2,6-dichlorophenylcarbonylamino)pyridine;

2-(2-methylcyclohexylamino)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2,4-dimethylphenylamino)-5-(2-fluorophenylcarbonyl amino)pyridine;

2-(2,4-dimethylphenylamino)-5-(2-chlorophenylcarbonyl amino)pyridine;

2-(2,4-dimethylphenylamino)-5-(2,6-dichlorophenylcarbonylamino)pyridine;

2-(2-methyl-4-chlorophenylamino)-5-(2,6-dichlorophenylcarbonylamino)pyridine;

2-(2,4-dimethylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2-methylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2-methylphenylamino)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;

2-(2-methylphenylamino)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;

2-(2,4-dimethylphenylamino)-5-(2,6-dimethylphenylcarbonylamino)pyridine;

2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenylcarbonylamino)pyridine;

2-(2-methyl-4-chlorophenylamino)-5-(2,6-dimethylphenylcarbonylamino)pyridine; and

2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenylaminocarbonyl)pyridine.

As utilized herein, the following terms shall have the followingmeanings:

“Alkyl”, alone or in combination, means a straight-chain orbranched-chain alkyl radical containing preferably 1-15 carbon atoms(C₁-C₁₅), more preferably 1-8 carbon atoms (C₁-C₈), even more preferably1-6 carbon atoms (C₁-C₆), yet more preferably 1-4 carbon atoms (C₁-C₄),still more preferably 1-3 carbon atoms (C₁-C₃), and most preferably 1-2carbon atoms (C₁-C₂). Examples of such radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,iso-amyl, hexyl, octyl and the like.

“Hydroxyalkyl”, alone or in combination, means an alkyl radical asdefined above wherein at least one hydrogen radical is replaced with ahydroxyl radical, preferably 1-3 hydrogen radicals are replaced byhydroxyl radicals, more preferably 1-2 hydrogen radicals are replaced byhydroxyl radicals, and most preferably one hydrogen radical is replacedby a hydroxyl radical. Examples of such radicals include hydroxymethyl,1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl,1,3-dihydroxybutyl, 1,2,3,4,5,6-hexahydroxy-2-hexyl and the like.

“Alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radical having one or more double bonds,preferably 1-2: double bonds and more preferably one double bond, andcontaining preferably 2-15 carbon atoms (C₂-C₁₅), more preferably 2-8carbon atoms (C₂-C₈), even more preferably 2-6 carbon atoms (C₂-C₆), yetmore preferably 2-4 carbon atoms (C₂-C₄), and still more preferably 2-3carbon atoms (C₂-C₃). Examples of such alkenyl radicals include ethenyl,propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.

“Alkoxy”, alone or in combination, means a radical of the type “R—O—”wherein “R” is an alkyl radical as defined above and “O” is an oxygenatom. Examples of such alkoxy radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy andthe like.

“Alkoxycarbonyl”, alone or in combination, means a radical of the type“R—O—C(O)—C(O)—” wherein “R—O—” is an alkoxy radical as defined aboveand “C(O)” is a carbonyl radical.

“Alkoxycarbonylamino”, alone or in combination, means a radical of thetype “R—O—C(O)—NH—” wherein “R—O—C(O)” is an alkoxycarbonyl radical asdefined above, wherein the amino radical may optionally be substituted,such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and thelike.

“Alkylthio”, alone or in combination, means a radical of the type “R—S—”wherein “R” is an alkyl radical as defined above and “S” is a sulfuratom. Examples of such alkylthio radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio and the like.

“Alkylsulfinyl”, alone or in combination, means a radical of the type“R—S(O)—” wherein “R” is an alkyl radical as defined above and “S(O)₂”is a mono-oxygenated sulfur atom. Examples of such alkylsulfinylradicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl,sec-butylsulfinyl, tert-butylsulfinyl and the like.

“Alkylsulfonyl”, alone or in combination, means a radical of the type“R—S(O)₂—” wherein “R” is an alkyl radical as defined above and “S(O)₂”is a di-oxygenated sulfur atom. Examples of such alkylsulfonyl radicalsinclude methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl,sec-butylsulfonyl, tert-butylsulfonyl and the like.

“Aryl”, alone or in combination, means a phenyl or biphenyl radical,which is optionally benzo fused or heterocyclo fused and which isoptionally substituted with one or more substituents selected fromalkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl,carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, amido, amidino,alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido,N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl,alkylsulfonyl, oxo and the like. Examples of aryl radicals are phenyl,o-tolyl, 4-methoxyphenyl, 2-(tert-butoxy)phenyl,3-methyl-4-methoxyphenyl, 2-CF₃-phenyl, 2-fluorophenyl, 2-chlorophenyl,3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl,2-amino-3-(aminomethyl)phenyl, 6-methyl-3-acetamidophenyl,6-methyl-2-aminophenyl, 6-methyl-2,3-diaminophenyl,2-amino-3-methylphenyl, 4,6-dimethyl-2-aminophenyl, 4-hydroxyphenyl,3-methyl-4-hydroxyphenyl, 4-(2-methoxyphenyl)phenyl, 2-amino-1-naphthyl,2-naphthyl, 3-amino-2-naphthyl, 1-methyl-3-amino-2-naphthyl,2,3-diamino-1-naphthyl, 4,8-dimethoxy-2-naphthyl and the like.

“Aralkyl” and “arylalkyl”, alone or in combination, means an alkylradical as defined above in which at least one hydrogen atom, preferably1-2, is replaced by an aryl radical as defined above, such as benzyl,1-, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl,methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl,4-methoxyphenylmethyl and the like.

“Aralkoxy”, alone or in combination, means an alkoxy radical as definedabove in which at least one hydrogen atom, preferably 1-2, is replacedby an aryl radical as defined above, such as benzyloxy, 1-,2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy,methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy andthe like.

“Aralkoxycarbonyl”, alone or in combination, means a radical of the type“R—O—C(O)—” wherein “R—O—” is an aralkoxy radical as defined above and“—C(O)—” is a carbonyl radical.

“Alkanoyl”, alone or in combination, means a radical of the type“R—C(O)—” wherein “R” is an alkyl radical as defined above and “—C(O)—”is a carbonyl radical. Examples of such alkanoyl radicals includeacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl,4-methylvaleryl, and the like.

“Alkanoylamino”, alone or in combination, means a radical of the type“R—C(O)—NH—” wherein “R—C(O)—” is an alkanoyl radical as defined above,wherein the amino radical may optionally be substituted, such as withalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.

“Aminocarbonyl”, alone or in combination, means an amino substitutedcarbonyl (carbamoyl) radical, wherein the amino radical may optionallybe mono- or di-substituted, such as with alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyland the like.

“Aminosulfonyl”, alone or in combination, means an amino substitutedsulfonyl radical.

“Benzo”, alone or in combination, means the divalent radical C₆H₄═derived from benzene. “Benzo fused” forms a ring system in which benzeneand a cycloalkyl or aryl group have two carbons in common, for exampletetrahydronaphthylene and the like.

“Bicyclic” as used herein is intended to include both fused ringsystems, such as naphthyl and β-carbolinyl, and substituted ringsystems, such as biphenyl, phenylpyridyl and diphenylpiperazinyl.

“Cycloalkyl”, alone or in combination, means a saturated or partiallysaturated, preferably one double bond, monocyclic, bicyclic or tricycliccarbocyclic alkyl radical, preferably monocyclic, containing preferably5-12 carbon atoms (C₅-C₁₂), more preferably 5-10 carbon atoms (C₅-C₁₀),even more preferably 5-7 carbon atoms (C₅-C₇), which is optionally benzofused or heterocyclo fused and which is optionally substituted asdefined herein with respect to the definition of aryl. Examples of suchcycloalkyl radicals include cyclopentyl, cyclohexyl,dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl,octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl,dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl,azabicyclo[3.2.1]octyl and the like.

“Heteroatoms” means nitrogen, oxygen and sulfur heteroatoms.

“Heterocyclo fused” forms a ring system in which a heterocyclyl orheteroaryl group of 5-6 ring members and a cycloalkyl or aryl group havetwo carbons in common, for example indole, isoquinoline,tetrahydroquinoline, methylenedioxybenzene and the like.

“Heterocyclyl” means a saturated or partially unsaturated, preferablyone double bond, monocyclic or bicyclic, preferably monocyclic,heterocycle radical containing at least one, preferably 1 to 4, morepreferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfuratom ring member and having preferably 3-8 ring members in each ring,more preferably 5-8 ring members in each ring and even more preferably5-6 ring members in each ring. “Heterocyclyl” is intended to includesulfone and sulfoxide derivatives of sulfur ring members and N-oxides oftertiary nitrogen ring members, and carbocyclic fused, preferably 3-6ring carbon atoms and more preferably 5-6 ring carbon atoms, and benzofused ring systems. “Heterocyclyl” radicals may optionally besubstituted on at least one, preferably 1-4, more preferably 1-3, evenmore preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy,oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino,N-alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like,and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl,alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals. Morepreferably, “heterocyclyl”, alone or in combination, is a radical of amonocyclic or bicyclic saturated heterocyclic ring system having 5-8ring members per ring, wherein 1-3 ring members are oxygen, sulfur ornitrogen heteroatoms, which is optionally partially unsaturated orbenzo-fused and optionally substituted by 1-2 oxo or thioxo radicals.Examples of such heterocyclyl radicals include pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl,4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl,pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl and itssulfoxide and sulfone derivatives, 2,3-dihydroindolyl,tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, 2,3-dihydrobenzofuryl,benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like.

“Heteroaryl” means a monocyclic or bicyclic, preferably monocyclic,aromatic heterocycle radical, having at least one, preferably 1 to 4,more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen orsulfur atom ring members and having preferably 5-6 ring members in eachring, which is optionally saturated carbocyclic fused, preferably 3-4carbon atoms (C₃-C₄) to form 5-6 ring membered rings and which isoptionally substituted as defined above with respect to the definitionsof aryl. Examples of such heteroaryl groups include imidazolyl,1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl, pyridyl,3-(2-methyl)pyridyl, 3-(4-trifluoromethyl)pyridyl, pyrimidinyl,5-(4-trifluoromethyl)pyrimidinyl, pyrazinyl, triazolyl, furyl, thienyl,oxazolyl, thiazolyl, indolyl, quinolinyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl,benzofuryl, benzimidiazolyl, benzoxazolyl and the like.

“Heteroaralkyl”, and “heteroarylalkyl,” alone or in combination, meansan alkyl radical as defined above in which at least one hydrogen atom,preferably 1-2, is replaced by a heteroaryl radical as defined above,such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl,2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.

“Halogen” and “halo”, alone or in combination, means fluoro, chloro,bromo or iodo radicals.

“Haloalkyl”, alone or in combination, means an alkyl radical as definedabove in which at least one hydrogen atom, preferably 1-3, is replacedby a halogen radical, more preferably fluoro or chloro radicals.Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl,chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, bis(trifluoromethyl)methyl and the like.

“Pharmacologically acceptable salt” means a salt prepared byconventional means, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid,tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid,maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelicacid and the like. When compounds of the invention include an acidicfunction such as a carboxy group, then suitable pharmaceuticallyacceptable cation pairs for the carboxy group are well known to thoseskilled in the art and include alkaline, alkaline earth, ammonium,quaternary ammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al, J.Pharm . Sci. 66, 1 (1977).

“Cytokine” means a secreted protein that affects the functions of othercells, particularly as it relates to the modulation of interactionsbetween cells of the immune system or cells involved in the inflammatoryresponse. Examples of cytokines include but are not limited tointerleukin 1 (IL-1), preferably IL-1β, interleukin 6 (IL-6),interleukin 8 (IL-8) and TNF, preferably TNF-α (tumor necrosisfactor-α).

“TNF, IL-1, IL-6, and/or IL-8 mediated disease or disease state” meansall disease states wherein TNF, IL-1, IL-6, and/or IL-8 plays a role,either directly as TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1,IL-6, and/or IL-8 inducing another cytokine to be released. For example,a disease state in which IL-1 plays a major role, but in which theproduction of or action of IL-1 is a result of TNF, would be consideredmediated by TNF.

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, arylalkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. A mixture of protecting groups can beused to protect the same amino group, such as a primary amino group canbe protected by both an aralkyl group and an aralkoxycarbonyl group.Amino protecting groups can also form a heterocyclic ring with thenitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.Amino groups may also be protected against undesired reactions, such asoxidation, through the formation of an addition salt, such ashydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.Many of the amino protecting groups are also suitable for protectingcarboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkylgroups are also sutiable groups for protecting hydroxy and mercaptogroups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-tri-silyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium flouride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydroylsis and hydrogenolysis conditions well known tothose skilled in the art.

The symbols used above have the following meanings:

—CR^(x)R^(y)— =

—C(O)— =

—NR^(x)R^(y) =

—C(NR)— =

—NR— =

—S(O)₂— =

Procedures for preparing the compounds of this invention are set forthbelow. It should be noted that the general procedures are shown as itrelates to preparation of compounds having unspecified stereochemistry.However, such procedures are generally applicable to those compounds ofa specific stereochemistry, e.g., where the stereochemistry about agroup is (S) or (R). In addition, the compounds having onestereochemistry (e.g., (R)) can often be utilized to produce thosehaving opposite stereochemistry (i.e., (S)) using well-known methods,for example, by inversion.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared utilizing the following general procedures.Hetero-aromatic Nitrogen Compounds; Pyrroles and Pyridines: Schofield,Kenneth; Plenum Press, New York, N.Y.; (1967) and Advances in NitrogenHeterocycles: JAI Press, Greenwich, Conn.; (1995) describe proceduresand references that may be useful in preparing compounds of the presentinvention.

2-Halo-5-nitro-pyridine analogs, (2) can be treated with the appropriateamine, alcohol, phenol, or thiol (R—X—H) in the presence of base orCu(I) in an appropriate solvent, such as THF, DMF, DME, DMSO and thelike, at a temperature from −20° C. to 120° C. to form2-substituted-5-nitropyridines (3) (Scheme I). Reduction of the nitrogroup can be perfomed by treatment of (3) with hydrogen gas in thepresence of palladium on carbon or Raney nickel, or alternatively, bytreatment with SnCl₂ in an alcoholic solvent and in the presence orabsence of HCl to obtain 2-substituted-5-aminopyridines (4). Theaminopyridines (4) may be alkylated using alkylhalides and anappropriate base or by reductive alkylation employing the appropriatealdehyde or ketone in the presence of a reducing agent, such as sodiumtriacetoxy borohydride, borane. THF and the like, to form thesubstituted aminopyridines (5). Either (4) or (5) may be acylated withan appropriate acid halide (e.g., R³C(O)Cl or R³C(O)Br) in the presenceof a base, such as pyridine, DMAP and the like, or alternatively may beacylated with an anhydride, either mixed or symmetrical, oralternatively may be acylated by treatment with the appropriate acid(R³CO₂H) in the presence of a coupling agent such as a carbodiimidereagent: to form the final product (1). Alternatively, substituted2-bromo-5-nitropyridine analogs may be reduced to, substituted2-bromo-5-aminopyridine analogs by the action of SnBr₂ in methanolicsolvent. Subsequent acylation with an appropriate activated ester (i.e.:R³CO₂H in the presence of diisopropylcarbodiimide in methylene chlorideas solvent) produces 2-bromopyridine-5-carboxamide compounds ofstructure (5a). Coupling of (5a) with an appropriate phenol in thepresence of Cu(Ac)₂ and K₂CO₃ in DMF at 140° C. provides compounds offormula (1) where X=O.

6-Substituted-2-halo-5-nitro-pyridine analogs (6) may be prepared from2,6-dichloro-5-nitropyridine 15 according to the methods outlined inScheme II. Treatment with one equivalent of an appropriate nucleophileof R⁷ or a precursor thereof (such as, HO⁻, RO⁻, AcS⁻, NC⁻, RS⁻ and thelike) provides (6). Subsequent reaction to form (7) (treatment withR¹—X—H in the presence of base or Cu(I) in an appropriate solvent, suchas THF, DMF, DME, DMSO and the like, at a temperature from —20° C. to120° C.) and (8) (reduction of the nitro group and substitution with R⁴)is as described in Scheme I (cf. Colbry, N. L. et al.; J. HeterocyclicChem., 21: 1521-1525 (1984); Matsumoto, Jun-ichi, et al.; J.Heterocyclic Chem., 21: 673-679 (1984)). (8) may be reacted with an acidhalide or an activated

ester as shown in Scheme I to provide compounds of formula (1). WhereR⁷═CN, compounds of formula (8) may be hydrolyzed to acids (R⁷═CO₂H) offormula (9) using acidic media such as HBr and the like. Utilizing theappropriate N-protecting groups, acids of formula (9) may be transformedinto esters, amides and alcohols. Compounds of formula (9) andderivatives described above may be be reacted with an acid halide or anactivated ester as shown in Scheme I to provide compounds of formula(1). Compounds of formula (8), where R⁷═—CN, may be reduced to theprimary amine (R⁷═—CH₂NH₂) using reagents such as BH₃ or hydrogen gas inthe presence of palladium on carbon or Raney nickel. Subsequentmanipulation and reaction of the primary amine may be performed in thepresence of the pyridine-5-amine substituent due to it's greaterreactivity. Specifically, compounds of formula (8) where R=—CH₂NH₂ maybe alkylated by treatment with an appropriate aldehyde or ketone in thepresence of a reducing agent, such as sodium triacetoxy borohydride, ormay be acylated by treatment with an appropriate activated ester,chloroformate, isocyanate and the like, or may be sulfonylated bytreatment with an appropriate sulfonyl halide. Alternatively,substituted 3-aminopyridine intermediates may be prepared from thecorresponding nicotinamide compound using Hofmann's reaction.

When R⁶ and/or R⁷ is an alkyl group, such as methyl, in compound (7),containing the appropriate protecting groups of or avoiding the presenceof base sensitive groups, can be treated with strong base such as NaNH₂,PhLi, NaH or the like at temperatures from −78° C. to 22° C. thentreated with electrophiles, such as alkyl halides, aldehydes, ketonesand the like (cf. Fuerst, Feustel; CHEMTECH; 10: 693-699 (1958);Nishigaki, S. et al.; Chem. Pharm. Bull.; 17: 1827-1831 (1969); Kaiser,Edwin M.; Tetrahedron; 39: 2055-2064 (1983)). Alternatively, the alkylgroup may be halogenated and the haloalkyl group may be reacted with anucleophile, such as an amino group, alkoxy, alkylthiol and the like.

6-Chloronicotinoyl chloride analogs (10) are treated with theappropriate amine (R³R⁴NH) in the presence of base in an appropriatesolvent, such as dichloromethane, acetonitrile, DMF, THF and the like,at a temperature from −20° C. to 120° C. to form nicotinamides (11) asshown in Scheme III. Alternatively, 6-chloronicotinic acid analogs (12)may be coupled with the appropriate amine via an anhydride, either mixedor symmetrical, or alternatively by treatment with the appropriate aminein the presence of a coupling agent such as a carbodiimide reagent toform the amide (11). 6-Chloronicotinamide analogs (11) are treated withthe appropriate R¹—X—H in the presence of absence of base, or Cu(I) inan approriate solvent, such as pyridine, ethylene glycol, DMF, DME, DMSOand the like, at a temperature from −20° C. to 180° C. to form the finalproduct (13).

Substituted halopyridines may be readily prepared from the correspondingpyridones using phosphorus oxychloride or pentachloride.

Amines of formula NHR¹R² and NHR³R⁴ are commercially available or can bereadily prepared by those skilled in the art from commercially availablestarting materials. For example, an amide, nitro or cyano group can bereduced under reducing conditions, such as in the prescence of areducing agent like lithium aluminum hydride and the like, to form thecorresponding amine. Alkylation and acylation of amino groups are wellknown in the art. Chiral and achiral substituted amines can be preparedfrom chiral amino acids and amino acid amides (for example, alkyl, aryl,heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andthe like) using methods well known in the art, such as H. Brunner, P.Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur. J.Med. Chem. 25, 35-44, 1990; M. Freifelder and R. B. Hasbrouck, J. Am.Chem. Soc. 82, 696-698, 1960; Dornow and Fust, Chem. Ber. 87, 985, 1954;M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459, 1982; W.Wheeler and D. O'Bannon, Journal of Labelled Compounds andRadiopharmaceuticals XXXI, 306, 1992; and S. Davies, N. Garrido, O.Ichihara and I. Walters, J. Chem. Soc., Chem., Commun. 1153, 1993.

Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonic acids,heteroaryl sulfonic acids, alkylmercaptans, arylmercaptans,heterocyclylmercaptans, heteroarylmercaptans, alkylhalides, arylhalides,heterocyclylhalides, heteroarylhalides, and the like are commerciallyavailable or can be readily prepared from starting materialscommercially available using standard methods well known in the art.

Thioether derivatives can be converted into the corresponding sulfone orsulfoxide by oxidizing the thioether derivative with a suitableoxidation agent in a suitable solvent. Suitable oxidation agentsinclude, for example, hydrogen peroxide, sodium meta-perborate, oxone(potassium peroxy monosulfate), meta-chloroperoxybenzoic acid, periodicacid and the like, including mixtures thereof. Suitable solvents includeacetic acid (for sodium meta-perborate) and, for other peracids, etherssuch as THF and dioxane, and acetonitrile, DMF and the like, includingmixtures thereof.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

Prodrugs of the compounds of this invention are also contemplated bythis invention A prodrug is an active or inactive compound that ismodified chemically through in vivo physicological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing adminstration of the prodrug to a patient. The suitability andtechniques involved in making and using prodrugs are well known by thoseskilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs,their preparation and use.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever. The followingExamples illustrate the preparation of compounds of the presentinvention and intermediates useful in preparing the compounds of thepresent invention.

EXAMPLE 1

Preparation of 2-(4-Chloro-2-methyl-phenoxy)-5-amino-pyridine

Step A: 2-(4-Chloro-2-methyl-phenoxy)-5-nitropyridine

4-Chloro-2-methylphenol (101 mg, 0.71 mmol) was dissolved intetrahydrofuran (2.1 mL) and the solution was treated with sodiumhydride (60% dispersed in mineral oil, 31 mg, 0.78 mmol). After stirringfor 30 minutes at 22° C., 2-chloro-5-nitropyridine (101 mg, 0.64 mmol)was added and the reaction mixture was heated to reflux for 1 hour. Thesolution was cooled to ambient temperature, quenched with saturatedaqueous NH₄Cl and concentrated in vacuo. The residue was redissolved inethyl acetate then washed 2× with saturated NaHCO₃, saturated NaCl,dried over anhydrous Na₂SO₄ and concentrated in vacuo.

Step B: 2-(4-Chloro-2-methyl-phenoxy)-5-amino-pyridine

2-(4-chloro-2-methyl-phenoxy)-5-nitropyridine (203 mg, 0.77 mmol) wasdissolved in 95% ethanol (3 mL) and treated with 20% palladium hydroxideon carbon (50 mg). The reaction mixture was shaken in a hydrogenatmosphere (40 psi) for 1 hour. The solution was filtered through celiteand concentrated in vacuo . MS (m/z): 234/236 (M+H)⁺; C₁₂H₁₁N₂OClrequires 234.7.

EXAMPLE 2

The compounds listed in Table 1 were prepared from2-chloro-5-nitropyridine and the appropriate alcohol, amine or thiol inthe same manner as 2-(4-Chloro-2-methyl-phenoxy)-5-amino-pyridine wasprepared.

TABLE 1 MS (m/z) 2-(4-Chloro-2-methylphenoxy)-5-amino-pyridine 2352-(4-Chloro-2,6-dimethylphenoxy)-5-amino- 249 pyridine2-(2-Methyl-pyridin-3-yloxy)-5-amino-pyridine 2012-(4-Fluoro-2-methylphenoxy)-5-amino-pyridine 2182-(2-Isopropylphenoxy)-5-amino-pyridine 2282-(1-Naphthyloxy)-5-amino-pyridine 2362-(Cyclohexyloxy)-5-amino-pyridine 1922-(2-Methylphenoxy)-5-amino-pyridine 2002-(2,4-Dimethylphenoxy)-5-amino-pyridine 2142-(4-Chlorophenoxy)-5-amino-pyridine 222 2-(Phenoxy)-5-amino-pyridine186 2-(2-Methylcyclohexylamino)-5-amino-pyridine 2052-(Cyclohexylamino)-5-amino-pyridine 1912-(2-Methylanilino)-5-amino-pyridine 1992-(4-Chloro-2-methylanilino)-5-amino-pyridine 2332-(2,4-Dimethylanilino)-5-amino-pyridine 2122-(4-Chloro-2-methylthiophenoxy)-5-amino- 251 pyridine

EXAMPLE 3

Preparation of 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-amino-pyridine

Step A: 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-nitropyridine

Sodium hydride (60% in mineral oil, 1.08 g, 27 mmol) was washed 3× withhexanes then a solution of 4-chloro-2-methylphenol (3.50 g, 24.5 mmol)dissolved in tetrahydrofuran (40 mL) was added. The solution was stirredfor 20 minutes then 2-chloro-3-methyl-5-nitropyridine (4.02 g, 23.3mmol) was added and the reaction mixture was heated to reflux for 3hours. After cooling, the mixture was concentrated in vacuo thendissolved in ethyl acetate and washed with water, 3× with saturatedNaHCO₃ and saturated NaCl then dried over Na₂SO₄and concentrated invacuo.

Step B: 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-amino-pyridine

2-(4-chloro-2-methyl-phenoxy)-3-methyl-5-nitropyridine (5.8 g, 20.8mmol) was dissolved in 95% ethanol (50 mL) and treated with 20%palladium hydroxide on carbon (350 mg). The reaction mixture was shakenin a hydrogen atmosphere (40 psi) for 1 hour. The solution was filteredthrough celite and concentrated in vacuo followed by chromatography onSiO₂ using 1:1 ethyl acetate/hexanes as eluant. MS (m/z): 248/250 (M+H)⁺C₁₃H₁₃N₂OCl requires 248.7.

EXAMPLE 4

The compounds listed in Table 2 were prepared from substituted2-chloro-5-nitropyridine and 4-chloro-2-methylphenol in the same manneras 2-(4-Chloro-2-methyl-phenoxy)-3-methyl-5-amino-pyridine was prepared.

TABLE 2 MS (m/z) 2-(4-Chloro-2-methyl-phenoxy)-4-methyl-5-amino- 249pyridine 6-(4-Chloro-2-methyl-phenoxy)-2-methyl-3-amino- 249 pyridine6-(4-Chloro-2-methyl-phenoxy)-2,3-diamino- 250 pyridine

EXAMPLE 5

Preparation of N-(2-(4-Chloro-2-methyl-phenoxy)-pyridin-5-yl)-benzamide

2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (211 mg, 0.90 mmol) wasdissolved in methylene chloride (2.7 mL) then treated with triethylamine(0.19 mL, 1.35 mmol) followed by benzoyl chloride (0.13 mL, 1.12 mmol).The reaction mixture was stirred for 3 hours at 22° C. then saturatedaqueous NaHCO₃ was added and the mixture was stirred for another hour.The organic layer was separated and washed 2× with 6% aqueous NaHCO₃,dried over Na₂SO₄ and concentrated in vacuo. The residue waschromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent.The product was recovered as a white solid. MS (m/z): 338/340 (M+H)⁺;C₁₉H₁₅N₂O₂Cl requires 338.8.

EXAMPLE 6

The compounds listed in Table 3 were prepared from substituted5-aminopyridine compounds and the appropriate acid chloride in the samemanner as N-(2-(4-Chloro-2 -methyl -phenoxy) -pyridin-5-yl)-benzamidewas prepared.

TABLE 3 MS (m/z) 2-(4-Chloro-2-methyl-phenoxy)-5-(3- 340pyridylcarbonylamino)pyridine 2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 408dichlorophenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-(4- 340 pyridylcarbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((4- 369methoxyphenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((4- 409pentylphenyl)carbonylamino)pyridine 2-(4-Chloro-2-methyl-phenoxy)-5-(2-389 naphthylcarbonylamino)pyridine 2-(4-Chloro-2-methyl-phenoxy)-5-(2-345 thienylcarbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((3,5-dimethyl- 3584-isoxazolyl)carbonylamino)pyridine 2-(4-Chloro-2-methyl-phenoxy)-5-((5-383 benzo[1,3]dioxol-yl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((5-tert-butyl- 3992-methyl-2H-pyrazol-3-yl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 395benzo[b]thiophenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 369methoxyphenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((3,5- 408dichlorophenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 367dimethylphenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 353methylphenyl)carbonylamino)pyridine 2-(4-Chloro-2-methyl-phenoxy)-5-((2-384 nitrophenyl)carbonylamino)pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 397acetoxyphenyl)carbonylamino)pyridine2-(4-chloro-2,6-dimethylphenoxy)-5-((2,6- 422dichlorophenyl)carbonylamino)pyridine2-(4-chloro-2,6-dimethylphenoxy)-5-((2,6- 381dimethylphenyl)carbonylamino)pyridine2-(2-methyl-pyridin-3-yloxy)-5-((2,6- 374dichlorophenyl)carbonylamino)pyridine2-(2-methyl-pyridin-3-yloxy)-5-((2,6- 333dimethylphenyl)carbonylamino)pyridine2-(2-methyl-pyridin-3-yloxy)-5-((2- 319methylphenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2,6- 391dichlorophenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2,6- 350dimethylphenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2- 336methylphenyl)carbonylamino)pyridine 2-(4-fluoro-2-methylphenoxy)-5-( (2-390 trifluoromethylphenyl)carbonylamino)pyridine2-(4-fluoro-2-methylphenoxy)-5-((2- 340 fluorophenyl)carbonylamino)pyridine 2-(2-isopropylphenoxy)-5-((2,6- 401dichlorophenyl)carbonylamino)pyridine 2-(2-isopropylphenoxy)-5-((2,6-360 dimethylphenyl)carbonylamino)pyridine 2-(2-isopropylphenoxy)-5-((2-346 methylphenyl)carbonylamino)pyridine 2-(1-naphthyloxy)-5-((2,6- 409dichlorophenyl)carbonylamino)pyridine 2-(1-naphthyloxy)-5-((2,6- 368dimethylphenyl)carbonylamino)pyridine 2-(1-naphthyloxy)-5-((2- 354methylphenyl)carbonylamino)pyridine 2-(cyclohexyloxy)-5-((2,6- 365dichlorophenyl)carbonylamino)pyridine 2-(cyclohexyloxy)-5-((2,6- 324dimethylphenyl)carbonylamino)pyridine 2-(cyclohexyloxy)-5-((2- 331chlorophenyl)carbonylamino)pyridine 2-(cyclohexyloxy)-5-((2- 310methylphenyl)carbonylamino)pyridine 2-(2-methylphenoxy)-5-((2,6- 373dichlorophenyl)carbonylamino)pyridine 2-(2-methylphenoxy)-5-((2,6- 332dimethylphenyl)carbonylamino)pyridine 2-(2-methylphenoxy)-5-((2- 339chlorophenyl)carbonylamino)pyridine 2-(2-methylphenoxy)-5-((2- 318methylphenyl)carbonylamino)pyridine 2-(2,4-dimethylphenoxy)-5-((2,6- 387dichlorophenyl)carbonylamino)pyridine 2-(2,4-dimethylphenoxy)-5-((2,6-346 dimethylphenyl)carbonylamino)pyridine 2-(2,4-dimethylphenoxy)-5-((2-353 chlorophenyl)carbonylamino)pyridine 2-(2,4-dimethylphenoxy)-5-((2-332 methylphenyl)carbonylamino)pyridine 2-(4-chlorophenoxy)-5-((2,6- 394dichlorophenyl)carbonylamino)pyridine 2-(4-chlorophenoxy)-5-((2,6- 353dimethylphenyl)carbonylamino)pyridine2-(2-methylcyclohexylamino)-5-((2,6- 378dichlorophenyl)carbonylamino)pyridine 2-(2-methylcyclohexylamino)-5-((2-323 methylphenyl)carbonylamino)pyridine 2-(cyclohexylamino)-5-((2,6- 364dichlorophenyl)carbonylamino)pyridine 2-(cyclohexylamino)-5-((2,6- 323dimethylphenyl)carbonylamino)pyridine 2-(cyclohexylamino)-5-((2- 309methylphenyl)carbonylamino)pyridine 2-(2-methylanilino)-5-((2,6- 372dichlorophenyl)carbonylamino)pyridine 2-(2-methylanilino)-5-(2,6- 331dimethylphenyl)carbonylamino)pyridine 2-(2-methylanilino)-5-((2- 317methylphenyl)carbonylamino)pyridine2-(4-chloro-2-methylanilino)-5-((2,6- 407dichlorophenyl)carbonylamino)pyridine2-(4-chloro-2-methylanilino)-5-((2,6- 366dimethylphenyl)carbonylamino)pyridine2-(4-chloro-2-methylanilino)-5-((2- 352methylphenyl)carbonylamino)pyridine 2-(2,4-dimethylanilino)5-((2,6- 386dichlorophenyl)carbonylamino)pyridine 2-(2,4-dimethylanilino)-5-((2,6-345 dimethylphenyl)carbonylamino)pyridine 2-(2,4-dimethylanilino)-5-((2-331 methylphenyl)carbonylamino)pyridine 2-(2,4-dimethylanilino)-5-((2-352 chlorophenyl)carbonylamino)pyridine 2-(2,4-dimethylanilino)-5-((2-335 fluorophenyl)carbonylamino)pyridine2-(4-chloro-2-methyl-thiophenyl)-5-((2,6- 424dichlorophenyl)carbonylamino)pyridine2-(4-chloro-2-methyl-thiophenyl)-5-((2,6- 383dimethylphenyl)carbonylamino)pyridine2-(4-chloro-2-methyl-thiophenyl)-5-((2- 369methylphenyl)carbonylamino)pyridine

EXAMPLE 7

The compounds listed in Table 4 were prepared from substituted5-aminopyridine compounds and the appropriate acid chloride in the samemanner as N-(2-(4-Chloro-2-methyl-phenoxy)-pyridin-5-yl)-benzamide wasprepared.

TABLE 4 MS (m/z) 2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 422dichlorophenyl)carbonylamino)-3-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 387chlorophenyl)carbonylamino)-3-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 367methylphenyl)carbonylamino)-3-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 332dimethylphenyl)carbonylamino)-3-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 422dichlorophenyl)carbonylamino)-4-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2-fluoro-6- 439trifluoromethylphenyl)carbonylamino-4-methyl- pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,4,6- 479triisopropylphenyl)carbonylamino)-4-methyl- pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 367methylphenyl)carbonylamino)-6-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 387chlorophenyl)carbonylamino)-6-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 422dichlorophenyl)carbonylamino)-6-methyl-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 423dichlorophenyl)carbonylamino)-6-amino-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 388chlorophenyl)carbonylamino)-6-amino-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2,6- 382dimethylphenyl)carbonylamino)-6-amino-pyridine2-(4-Chloro-2-methyl-phenoxy)-5-((2- 368methylphenyl)carbonylamino)-6-amino-pyridine

EXAMPLE 8

Preparation of2-Amino-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-benzamide

N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-2-nitro-benzamide (301mg, 0.7 mmol) was dissolved in 95% ethanol (4 mL) and treated with 20%palladium hydroxide on carbon (Pearlman's catalyst, 50 mg) and subjectedto a hydrogen atmosphere (40 psi) for 2 hours. The catalyst was removedby filtration and the solvents were removed in vacuo. The product waspurified by chromatography on SiO2 using 1:1 ethyl acetate/hexanes aseluent. MS (m/z): 353/355 (M+H)⁺; C₁₉H₁₆N₃O₂Cl requires 353.8.

EXAMPLE 9

Preparation ofN-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-2-hydroxy-benzamide

Acetic acid2-(6-(4-chloro-2-methyl.-phenoxy)-pyridin-3-ylcarbamoyl)-phenyl ester(304 mg, 0.77 mmol) dissolved in tetrahydrofuran (3.8 mL) was treatedwith an aqueous lithium hydroxide solution (1.0 M, 3.8 mL, 3.8 mmol).The solution was stirred for 30 minutes at 22° C. then quenched withaqueous saturated NH₄Cl. The mixture was diluted with ethyl acetate thenthe organics were washed with water, 2× saturated NaHCO₃, saturatedNaCl, dried over Na₂SO₄ and concentrated in vacuo. MS (m/z): 354/356(M+H)⁺; C₁₉H₁₅N₂O₃Cl requires 354.8.

EXAMPLE 10

Preparation of 2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine

Step A: 2-(Cyclohexylamino)-5-nitro-pyridine

Sodium hydride (60% dispersion in mineral oil, 1.99 g, 49.8 mmol) waswashed 3× with hexanes then a solution of cyclohexylamine (3.8 mL, 33.2mmol) dissolved in tetrahydrofuran (50 mL) was added. After stirring for30 minutes at 22° C., 2-chloro-5-nitropyridine (5.00 g, 31.5 mmol) wasadded and the reaction mixture was heated to reflux for 3 hours. Thesolution was cooled to ambient temperature, quenched with saturatedaqueous NH₄Cl and concentrated in vacuo. The residue was redissolved inethyl acetate then washed 2× with saturated NaHCO₃, saturated NaCl,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The product wasrecovered as a brown oil.

Step B: 2-(N-Cyclohexyl-N-methylamino)-5-nitro-pyridine

Sodium hydride (60% dispersion in mineral oil, 0.38 g, 9.48 mmol) waswashed 3× with hexanes then a solution of2-cyclohexylamino-5-nitropyridine (1.88 g, 8.5 mmol) dissolved indimethylformamide (20 mL) was added. After stirring for 30 minutes at22° C., the reaction mixture was cooled to 0° C. and methyl iodide (0.55mL, 8.9 mmol) was added. The solution was stirred for 1.5 hours at 0° C.followed by quenching with saturated aqueous NH₄Cl. The reaction mixturewas diluted with ethyl acetate and extracted 5× with water (200 mL),saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo oil waschromatographed on SiO₂ using 2:1 hexanes/ethyl acetate as eluent.

Step C: 2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine

Cyclohexyl-methyl-(5-nitro-pyridin-2-yl)-amine (1.72 g, 7.3 mmol) wasdissolved in ethanol (80 mL) and treated with 20% palladium hydroxide oncarbon (Pearlman's catalyst, 0.5 g) and the mixture was shaken under ahydrogen atmosphere (50 psi) for 6 hours. The catalyst was removed byfiltration through celite then the filtrate was concentrated in vacuoand the resultant oil was chromotographed on SiO₂ using 1:1 ethylacetate/hexanes as eluent. MS (m/z): 206 (M+H)⁺; C₁₂H₁₉N₃ requires205.3.

EXAMPLE 11

Preparation of2-(N-(2,4-dimethyl-phenyl)-N-methylamino)-5-amino-pyridine

2-(N-(2,4-dimethylphenyl)-N-methylamino)-5-amino-pyridine was preparedfrom 1-amino-2,4-dimethylbenzene and 2-chloro-5-nitropyridine in thesame manner as 2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine wasprepared.

EXAMPLE 12

Preparation of2,6-Dichloro-N-(2-(N′-cyclohexyl-N′-methylamino)-pyridin-5-yl)-benzamide

2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine (26 mg, 0.13 mmol)dissolved in methylene chloride (0.25 mL) was treated with triethylamine(0.026 mL, 0.18 mmol) followed by a solution of 2,6-dichlorobenzoylchloride (31 mg, 0.15 mmol) dissolved in methylene chloride (0.15 mL).The reaction mixture was shaken at 22° C. for 18 hours followed byquenching with saturated aqueous NH₄Cl and stirring for an additional 5hours. The organic layer was separated and dried over Na₂SO₄ thenconcentrated in vacuo. The crude product was purified by chromatographyon SiO₂ using 1:1 ethyl acetate/hexane as eluent. MS (m/z): 378/380(M+H)⁺; C₁₉H₂₁N₃OC; requires 377.

EXAMPLE 13

The compounds listed in Table 5 were prepared from substituted5-aminopyridine compounds and the appropriate acid chloride in the samemanner as2,6-Dichloro-N-(2-(N′-cyclohexyl-N′-methylamino)-pyridin-5-yl)-benzamidewas prepared.

TABLE 5 MS (m/z) 2-(N-cyclohexyl-N-methylamino)-5-((2,6- 378dichlorophenyl)carbonylamino)pyridine2-(N-cyclohexyl-N-methylamino)-5-((2- 344chlorophenyl)carbonylamino)pyridine2-(N-cyclohexyl-N-methylamino)-5-((2- 323methylphenyl)carbonylamino)pyridine2-(N-cyclohexyl-N-methylamino)-5-((2,6- 337dimethylphenyl)carbonylamino)pyridine 2-(2,4-dimethylphenyl)-5-((2,6-359 dimethylphenyl)carbonylamino)pyridine 2-(2,4-dimethylphenyl)-5-((2-345 methylphenyl)carbonylamino)pyridine 2-(2,4-dimethylphenyl)-5-((2-366 chlorophenyl)carbonylamino)pyridine 2-(2,4-dimethylphenyl)-5-((2-349 fluorophenyl)carbonylamino)pyridine 2-(2,4-dimethylphenyl)-5-((2,6-400 dichlorophenyl)carbonylamino)pyridine

EXAMPLE 14

Preparation of 2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine

2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (2.15 g, 9.16 mmol) wascombined with powdered sodium hydroxide (1.46 g, 36.6 mmol), potassiumcarbonate (1.27 g, 9.16 mmol), tetrabutyl ammonium bromide (60 mg, 0.18mmol) and toluene (10 mL) was stirred for 1 hour at 35° C. A solution ofdimethyl sulfate (0.91 mL, 9.6 mmol) dissolved in toluene (5 mL) wasadded slowly. The mixture was heated at 35° C. for 20 hours. Aftercooling, the solids were removed by filtration and the solvent wasconcentrated in vacuo. The desired material was purified bychromatography on SiO₂ using 30% ethyl acetate / hexanes as eluent. MS(m/z): 248/250 (M+H)⁺; C₁₃H₁₃N₂OCl requires 249.

EXAMPLE 15

Preparation of 26-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide

2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine (32 mg, 0.13mmol) dissolved in methylene chloride (0.25 mL) was treated withtriethylamine (0.026 mL, 0.18 mmol) followed by a solution of2,6-dichlorobenzoyl chloride (31 mg, 0.15 mmol) dissolved in methylenechloride (0.15 mL). The reaction mixture was shaken at 22° C. for 18hours followed by quenching with saturated aqueous NH₄Cl and stirringfor an additional 5 hours. The organic layer was separated and driedover Na₂SO₄ then concentrated in vacuo. The crude product was purifiedby chromatography on SiO₂ using 1:1 ethyl acetate/hexane as eluent. MS(m/z): 422/424 (M+H)⁺; C₂₀H₁₅N₂O₂Cl₃ requires 422.

EXAMPLE 16

Preparation of2-Chloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide

2-Chloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamidewas prepared from2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine and2-chlorobenzoyl chloride in the same manner as2,6-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamidewas prepared.

EXAMPLE 17

Preparation of2-Methyl-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide

2-Methyl-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamidewas prepared from2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine and2-methylbenzoyl chloride in the same manner as2,6-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamidewas prepared.

EXAMPLE 18

General procedure for the synthesis of2-substituted-5-acylamino-pyridines

A solution of the 2-substituted-5-aminopyridine (10 mmol), triethylamine(20 mmol) and an acid chloride (20 mmol) in ethanol free chloroform (250mL) was shaken for 16 hours. The mixture was then diluted with saturatedaqueous sodium hydrogencarbonate (50 mL) and dichloromethane (500 mL),and shaken for 30 min. The mixture was then filtered through anhydrousmagnesium sulfate, washing with dichloromethane (250 mL). Concentrationof the filtrate under reduced pressure afforded the desired2-substituted-5-acylamino-pyridines.

The compounds listed in Table 6 were prepared from substituted5-aminopyridine compounds and the appropriate acid chloride according tothe general procedure above.

TABLE 6 MS R¹X R³ (m/z) 4-chloro-2- 4-biphenyl 415 methylphenoxy4-chloro-2- 3,4-dimethoxyphenyl 319 methylphenoxy 4-chloro-2-2-(trifluoromethyl)phenyl 407 methylphenoxy 4-chloro-2-2,4-difluorophenyl 375 methylphenoxy 4-chloro-2- 4-cyanophenyl 364methylphenoxy 4-chloro-2- 3-(trifluoromethyl)phenyl 407 methylphenoxy4-chloro-2- 3-cyanophenyl 364 methylphenoxy 4-chloro-2- 2-naphthyl 389methylphenoxy 4-chloro-2- 2-methoxyphenyl 369 methylphenoxy 4-chloro-2-3,4,5-trimethylphenyl 429 methylphenoxy 4-chloro-2- 4-nitrophenyl 384methylphenoxy 4-chloro-2- 3,4-dichlorophenyl 408 methylphenoxy4-chloro-2- 5-nitrofuran-2-yl 374 methylphenoxy 4-chloro-2-3-bromophenyl 418 methylphenoxy 4-chloro-2- 3-pyridyl 340 methylphenoxy4-chloro-2- 2-ethoxynaphth-1-yl 433 methylphenaxy 4-chloro-2-2,3-dichlorophenyl 408 methylphenoxy 4-chloro-2- 3-nitrophenyl 384methylphenoxy 4-chloro-2- 6-chloropyrid-3-yl 374 methylphenoxy4-chloro-2- 4-(trifluoromethoxy)phenyl 423 methylphenoxy 4-chloro-2-2-fluoro-4- 425 methylphenoxy (trifluoromethyl)phenyl 4-chloro-2-2-acetoxyphenyl 397 methylphenoxy 4-chloro-2- 5-methylisoxazol-3-yl 344methylphenoxy 4-chloro-2- 2-(phenylthio)pyrid-3-yl 448 methylphenoxy4-chloro-2- 2-(trifluoromethoxy)phenyl 423 methylphenoxy 4-chloro-2-1-phenyl-5-propyl-pyrazin- 447 methylphenoxy 4-yl 4-chloro-2-2-ethoxyphenyl 383 methylphenoxy 4-chloro-2- 3-chlorothien-2-yl 379methylphenoxy 4-chloro-2- 3-bromothien-2-yl 424 methylphenoxy4-chloro-2- 1-(2-(2-methyl)propyl)-3- 399 methylphenoxymethylpyrazol-5-yl 4-chloro-2- 3,5-dichlorophenyl 408 methylphenoxy4-chloro-2- 2-(propylthio)pyridin-3-yl- 414 methylphenoxy 4-chloro-2-2-(ethylthio)pyridin-3-yl 400 methylphenoxy 4-chloro-2-3-bromopyridin-5-yl 419 methylphenoxy 4-chloro-2-4-methyl-1,2,3-thiadiazol 361 methylphenoxy 5-yl 4-chloro-2-1-methyl-3-(2-(2- 399 methylphenoxy methyl)propyl)pyrazol-5-yl4-chloro-2- 3-chlorobenzo[b]thiophen- 429 methylphenoxy 2-yl 4-chloro-2-4-chlorophenyl 373 methylphenoxy 4-chloro-2- 4-methyl-2-phenyl-1,2,3-420 methylphenoxy triazol-5-yl 4-chloro-2- benzo[b]thiophen-2-yl 395methylphenoxy 4-chloro-2- 3,4-dimethylphenyl 367 methylphenoxy4-chloro-2- 2-(phenoxy)pyridin-3-yl 432 methylphenoxy 4-chloro-2-2-(methylthio)pyridin-3-yl 386 methylphenoxy 4-chloro-2-5-methyl-3-phenylisoxazol- 420 methylphenoxy 4-yl 4-chloro-2-4-chloro-1,3-dimethyl 442 methylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-2- 2-chloro-6-methylpyridin- 388 methylphenoxy 4-yl 4-chloro-2-3,5-dimethylisoxazol-4-yl 358 methylphenoxy 4-chloro-2- 1-naphthyl 389methylphenoxy 4-chloro-2- 2-fluorophenyl 357 methylphenoxy 4-chloro-2-4-propylphenyl 381 methylphenoxy 4-chloro-2- 4-(trifluoromethyl)phenyl407 methylphenoxy 4-chloro-2- 3-fluorophenyl 357 methylphenoxy4-chloro-2- 2,6-difluorophenyl 375 methylphenoxy 4-chloro-2-2-chlorophenyl 373 methylphenoxy 4-chloro-2- 3-(chloromethyl)phenyl 387methylphenoxy 4-chloro-2- 4-(2-(2-methyl) 395 methylphenoxypropyl)phenyl 4-chloro-2- 3-chlorophenyl 373 methylphenoxy 4-chloro-2-2-nitrophenyl 384 methylphenoxy 4-chloro-2- 3,5-dimethoxyphenyl 399methylphenoxy 4-chloro-2- 2,6-dichlorophenyl 408 methylphenoxy4-chloro-2- 2,4-dichlorophenyl 408 methylphenoxy 4-chloro-2-4-fluorophenyl 357 methylphenoxy 4-chloro-2- 4-butylphenyl 395methylphenoxy 4-chloro-2- 2-methylphenyl 353 methylphenoxy 4-chloro-2-phenyl 339 methylphenoxy 4-chloro-2- 4-ethylphenyl 367 methylphenoxy4-chloro-2- 2,3-difluorophenyl 375 methylphenoxy 4-chloro-2-2,6-dimethoxyphenyl 399 methylphenoxy 4-chloro-2- 2,5-difluorophenyl 375methylphenoxy 4-chloro-2- 4-ethoxyphenyl 383 methylphenoxy 4-chloro-2-2,4,6-trichlorophenyl 442 methylphenoxy 4-chloro-2- 3-methylphenyl 353methylphenoxy 4-chloro-2- 2-fluoro-5- 425 methylphenoxy(trifluoromethyl)phenyl 4-chloro-2- 3-methoxyphenyl 369 methylphenoxy4-chloro-2- thien-2-yl 345 methylphenoxy 4-chloro-2- 2-bromophenyl 418methylphenoxy 4-chloro-2- 4-bromophenyl 418 methylphenoxy 4-chloro-2-4-fluoro-3- 425 methylphenoxy (trifluoromethyl)phenyl 4-chloro-2-3-(trifluoromethoxy)phenyl 423 methylphenoxy 4-chloro-2-9-fluorenon-4-yl 441 methylphenoxy 4-chloro-2- isoxazol-5-yl 330methylphenoxy 4-chloro-2- benzofuroxan-5-yl 397 methylphenoxy4-chloro-2- 2-chloropyrid-3-yl 374 methylphenoxy 4-chloro-2-3,5-difluorophenyl 375 methylphenoxy 4-chloro-2- 2-(4- 446 methylphenoxymethylphenoxy)pyridin-3-yl 4-chloro-2- pyridin-4-yl 340 methylphenoxy4-chloro-2- anthraquinon-2-yl 469 methylphenoxy 4-chloro-2- 2-iodophenyl465 methylphenoxy 1-naphthoxy 4-biphenyl 416 1-naphthoxy3,4-dimethoxyphenyl 400 1-naphthoxy 2-(trifluoromethyl)phenyl 4081-naphthoxy 2,4-difluorophenyl 376 1-naphthoxy 4-cyanophenyl 3651-naphthoxy 3-(trifluoromethyl)phenyl 408 1-naphthoxy 3-cyanophenyl 3651-naphthoxy 2-naphthyl 390 1-naphthoxy 2-methoxyphenyl 370 1-naphthoxy3,4,5-trimethylphenyl 430 1-naphthoxy 4-nitrophenyl 385 1-naphthoxy3,4-dichlorophenyl 409 1-naphthoxy 5-nitrofuran-2-yl 375 1-naphthoxy3-bromophenyl 419 1-naphthoxy 3-pyridyl 341 1-naphthoxy2-ethoxynaphth-1-yl 334 1-naphthoxy 2,3-dichlorophenyl 409 1-naphthoxy3-nitrophenyl 385 1-naphthoxy 6-chloropyrid-3-yl 376 1-naphthoxy4-(trifluoromethoxy)phenyl 424 1-naphthoxy 2-fluoro-4- 426(trifluoromethyl)phenyl 1-naphthoxy 3-bromothiophenyl 425 1-naphthoxy2-acetoxyphenyl 398 1-naphthoxy 5-methylisoxazol-3-yl 345 1-naphthoxy2-(phenylthio)pyrid-3-yl 449 1-naphthoxy 2-(trifluoromethoxy)phenyl 4241-naphthoxy 1-phenyl-5-propylpyrazin- 448 4-yl 1-naphthoxy2-ethoxyphenyl 384 1-naphthoxy 3-chlorothien-2-yl 381 1-naphthoxy1-(2-(2-methyl)propyl)-3- 400 methylpyrazol-5-yl 1-naphthoxy3,5-dichlorophenyl 409 1-naphthoxy 2-(propylthio)pyridin-3-yl 4151-naphthoxy 2-(ethylthio)pyridin-3-yl 401 1-naphthoxy3-bromopyridin-5-yl 420 1-naphthoxy 4-methyl-1,2,3-thiadiazol- 362 5-yl1-naphthoxy 1-methyl-3-(2-(2- 400 methyl)propyl)pyrazol-5-yl 1-naphthoxy3-chlorobenzo[b]thiophen- 431 2-yl 1-naphthoxy 4-chlorophenyl 3751-naphthoxy 4-methyl-2-phenyl-1,2,3- 421 triazol-5-yl 1-naphthoxybenzo[b]thiophen-2-yl 396 1-naphthoxy 3,4-dimethylphenyl 368 1-naphthoxy2-(phenoxy)pyridin-3-yl 433 1-naphthoxy 2-(methylthio)pyridin-3-yl 3871-naphthoxy 5-methyl-3-phenylisoxazol- 421 4-yl 1-naphthoxy4-chloro-1,3-dimethyl 444 pyrazolo[3,4-b]pyridin-3- yl 1-naphthoxy2-chloro-6-methylpyridin- 390 4-yl 1-naphthoxy 3,5-dimethylisoxazol-4-yl359 1-naphthoxy 1-naphthyl 390 1-naphthoxy 2-fluorophenyl 3581-naphthoxy 4-propylphenyl 382 1-naphthoxy 4-(trifluoromethyl)phenyl 4081-naphthoxy 3-fluorophenyl 358 1-naphthoxy 2,6-difluorophenyl 3761-naphthoxy 2-chlorophenyl 375 1-naphthoxy 3-(chloromethyl)phenyl 3891-naphthoxy 4-(2-(2- 396 methyl)propyl)phenyl 1-naphthoxy 3-chlorophenyl375 1-naphthoxy 2-nitrophenyl 385 1-naphthoxy 3,5-dimethoxyphenyl 4001-naphthoxy 2,6-dichlorophenyl 409 1-naphthoxy 2,4-dichlorophenyl 4091-naphthoxy 4-fluorophenyl 358 1-naphthoxy 4-butylphenyl 396 1-naphthoxy2-methylphenyl 354 1-naphthoxy phenyl 340 1-naphthoxy 4-ethylphenyl 3681-naphthoxy 2,3-difluorophenyl 376 1-naphthoxy 2,6-dimethoxyphenyl 4001-naphthoxy 3,4-difluorophenyl 376 1-naphthoxy 2,5-difluorophenyl 3761-naphthoxy 4-ethoxyphenyl 384 1-naphthoxy 2,4,6-trichlorophenyl 4441-naphthoxy 3-methylphenyl 354 1-naphthoxy 2-fluoro-5- 426(trifluoromethyl)phenyl 1-naphthoxy 3-methoxyphenyl 370 1-naphthoxythien-2-yl 346 1-naphthoxy 2-bromophenyl 419 1-naphthoxy 4-bromophenyl419 1-naphthoxy 4-fluoro-3- 426 (trifluoromethyl)phenyl 1-naphthoxy3-(trifluoromethoxy)phenyl 424 1-naphthoxy 9-fluorenon-4-yl 4421-naphthoxy isoxazol-5-yl 331 1-naphthoxy benzofuroxan-5-yl 3981-naphthoxy 2-chloropyrid-3-yl 376 1-naphthoxy 3,5-difluorophenyl 3761-naphthoxy 2-(4- 447 methylphenoxy)pyridin-3-yl 1-naphthoxypyridin-4-yl 341 1-naphthoxy anthraquinon-2-yl 470 1-naphthoxy2-iodophenyl 466 2-(2-propyl)phenoxy 4-biphenyl 408 2-(2-propyl)phenoxy3,4-dimethoxyphenyl 392 2-(2-propyl)phenoxy 2-(trifluoromethyl)phenyl400 2-(2-propyl)phenoxy 2,4-difluorophenyl 368 2-(2-propyl)phenoxy4-cyanophenyl 357 2-(2-propyl)phenoxy 3-(trifluoromethyl)phenyl 4002-(2-propyl)phenoxy 3-cyanophenyl 357 2-(2-propyl)phenoxy 2-naphthyl 3822-(2-propyl)phenoxy 2-methoxyphenyl 362 2-(2-propyl)phenoxy3,4,5,-trimethylphenyl 422 2-(2-propyl)phenoxy 4-nitrophenyl 3772-(2-propyl)phenoxy 3,4-dichlorophenyl 401 2-(2-propyl)phenoxy5-nitrofuran-2-yl 367 2-(2-propyl)phenoxy 3-bromophenyl 4112-(2-propyl)phenoxy 3-pyridyl 333 2-(2-propyl)phenoxy2-ethoxynaphth-1-yl 426 2-(2-propyl)phenoxy 2,3-dichlorophenyl 4012-(2-propyl)phenoxy 3-nitrophenyl 377 2-(2-propyl)phenoxy6-chloropyrid-3-yl 368 2-(2-propyl)phenoxy 4-(trifluoromethoxy)phenyl416 2-(2-propyl)phenoxy 2-fluoro-4- 418 (trifluoromethyl)phenyl2-(2-propyl)phenoxy 3-bromothiophenyl 417 2-(2-propyl)phenoxy2-acetoxyphenyl 390 2-(2-propyl)phenoxy 5-methylisoxazol-3-yl 3372-(2-propyl)phenoxy 2-(phenylthio)pyrid-3-yl 442 2-(2-propyl)phenoxy2-(trifluoromethoxy)phenyl 416 2-(2-propyl)phenoxy1-phenyl-5-propylpyrazin- 441 4-yl 2-(2-propyl)phenoxy 2-ethoxyphenyl376 2-(2-propyl)phenoxy 3-chlorothien-2-yl 373 2-(2-propyl)phenoxy1-(2-(2-methyl)propyl)-3- 392 methylpyrazol-5-yl 2-(2-propyl)phenoxy3,5-dichlorophenyl 401 2-(2-propyl)phenoxy 2-(propylthio)pyridin-3-yl407 2-(2-propyl)phenoxy 2-(ethylthio)pyridin-3-yl 3932-(2-propyl)phenoxy 3-bromopyridin-5-yl 412 2-(2-propyl)phenoxy4-methyl-1,2,3-thiadiazol- 354 5-yl 2-(2-propyl)phenoxy1-methyl-3-(2-(2- 392 methyl)propyl)pyrazol-5-yl 2-(2-propyl)phenoxy3-chlorobenzo[b]thiophen- 423 2-yl 2-(2-propyl)phenoxy 4-chlorophenyl367 2-(2-propyl)phenoxy 4-methyl-2-phenyl-1,2,3- 413 triazol-5-yl2-(2-propyl)phenoxy benzo[b]thiophen-2-yl 388 2-(2-propyl)phenoxy3,4-dimethylphenyl 360 2-(2-propyl)phenoxy 2-(phenoxy)pyridin-3-yl 4252-(2-propyl)phenoxy 2-(methylthio)pyridin-3-yl 379 2-(2-propyl)phenoxy5-methyl-3-phenylisoxazol- 413 4-yl 2-(2-propyl)phenoxy 4-chloro-1,3-436 dimethylpyrazolo[3,4- b]pyridin-3-yl 2-(2-propyl)phenoxy2-chloro-6-methylpyridin- 382 4-yl 2-(2-propyl)phenoxy3,5-dimethylisoxazol-4-yl 351 2-(2-propyl)phenoxy 1-naphthyl 3822-(2-propyl)phenoxy 2-fluorophenyl 350 2-(2-propyl)phenoxy4-propylphenyl 374 2-(2-propyl)phenoxy 4-(trifluoromethyl)phenyl 4002-(2-propyl)phenoxy 3-fluorophenyl 350 2-(2-propyl)phenoxy2,6-difluorophenyl 368 2-(2-propyl)phenoxy 2-chlorophenyl 3672-(2-propyl)phenoxy 3-(chloromethyl)phenyl- 381 2-(2-propyl)phenoxy4-(2-(2- 388 methyl)propyl)phenyl 2-(2-propyl)phenoxy 3-chlorophenyl 3672-(2-propyl)phenoxy 2-nitrophenyl 377 2-(2-propyl)phenoxy3,5-dimethoxyphenyl 392 2-(2-propyl)phenoxy 2,6-dichlorophenyl 4012-(2-propyl)phenoxy 2,4-dichlorophenyl 401 2-(2-propyl)phenoxy4-fluorophenyl 350 2-(2-propyl)phenoxy 4-butylphenyl 3882-(2-propyl)phenoxy 2-methylphenyl 346 2-(2-propyl)phenoxy phenyl 3322-(2-propyl)phenoxy 4-ethylphenyl 360 2-(2-propyl)phenoxy2,3-difluorophenyl 368 2-(2-propyl)phenoxy 2,6-dimethoxyphenyl 3922-(2-propyl)phenoxy 3,4-difluorophenyl 368 2-(2-propyl)phenoxy2,5-difluorophenyl 368 2-(2-propyl)phenoxy 4-ethoxyphenyl 3762-(2-propyl)phenoxy 2,4,6-trichlorophenyl 436 2-(2-propyl)phenoxy3-methylphenyl 346 2-(2-propyl)phenoxy 2-fluoro-5- 418(trifluoromethyl)phenyl 2-(2-propyl)phenoxy 3-methoxyphenyl 3622-(2-propyl)phenoxy thien-2-yl 338 2-(2-propyl)phenoxy 2-bromophenyl 4112-(2-propyl)phenoxy 4-bromophenyl 411 2-(2-propyl)phenoxy 4-fluoro-3-418 (trifluoromethyl)phenyl 2-(2-propyl)phenoxy3-(trifluoromethoxy)phenyl 416 2-(2-propyl)phenoxy 9-fluorenon-4-yl 4342-(2-propyl)phenoxy isoxazol-5-yl 323 2-(2-propyl)phenoxybenzofuroxan-5-yl 390 2-(2-propyl)phenoxy 2-chloropyrid-3-yl 3682-(2-propyl)phenoxy 3,5-difluorophenyl 368 2-(2-propyl)phenoxy 2-(4- 439methylphenoxy)pyridin-3-yl 2-(2-propyl)phenoxy pyridin-4-yl 3332-(2-propyl)phenoxy anthraquinon-2-yl 462 2-(2-propyl)phenoxy2-iodophenyl 458 3-fluoro-5- 4-biphenyl 398 methylphenoxy 3-fluoro-5-3,4-dimethoxyphenyl 382 methylphenoxy 3-fluoro-5-2-(trifluoromethyl)phenyl 390 methylphenoxy 3-fluoro-5-2,4-difluorophenyl 358 methylphenoxy 3-fluoro-5- 4-cyanophenyl- 347methylphenoxy 3-fluoro-5- 3-(trifluoromethyl)phenyl 390 methylphenoxy3-fluoro-5- 3-cyanophenyl 347 methylphenoxy 3-fluoro-5- 2-naphthyl 372methylphenoxy 3-fluoro-5- 2-methoxyphenyl- 352 methylphenoxy 3-fluoro-5-3,4,5,-trimethylphenyl 412 methylphenoxy 3-fluoro-5- 4-nitrophenyl 367methylphenoxy 3-fluoro-5- 3,4-dichlorophenyl 391 methylphenoxy3-fluoro-5- 5-nitrofuran-2-yl 357 methylphenoxy 3-fluoro-5-3-bromophenyl 401 methylphenoxy 3-fluoro-5- 3-pyridyl 323 methylphenoxy3-fluoro-5- 2-ethoxynaphth-1-yl 416 methylphenoxy 3-fluoro-5-2,3-dichlorophenyl 391 methylphenoxy 3-fluoro-5- 3-nitrophenyl 367methylphenoxy 3-fluoro-5- 6-chloropyrid-3-yl 358 methylphenoxy3-fluoro-5- 4-(trifluoromethoxy)phenyl 406 methylphenoxy 3-fluoro-5-2-fluoro-4- 408 methylphenoxy (trifluoromethyl)phenyl 3-fluoro-5-3-bromothienyl 407 methylphenoxy 3-fluoro-5- 2-acetoxyphenyl 380methylphenoxy 3-fluoro-5- 5-methylisoxazol-3-yl 327 methylphenoxy3-fluoro-5- 2-(phenylthio)pyrid-3-yl 431 methylphenoxy 3-fluoro-5-2-(trifluoromethoxy)phenyl 406 methylphenoxy 3-fluoro-5-1-phenyl-5-propylpyrazin- 430 methylphenoxy 4-yl 3-fluoro-5-2-ethoxyphenyl 366 methylphenoxy 3-fluoro-5- 3-chlorothien-2-yl 363methylphenoxy 3-fluoro-5- 1-(2-(2-methyl)propyl)-3- 382 methylphenoxymethylpyrazol-5-yl 3-fluoro-5- 3,5-dichlorophenyl- 391 methylphenoxy3-fluoro-5- 2-(propylthio)pyridin-3-yl 397 methylphenoxy 3-fluoro-5-2-(ethylthio)pyridin-3-yl 383 methylphenoxy 3-fluoro-5-3-bromopyridin-5-yl 402 methylphenoxy 3-fluoro-5-4-methyl-1,2,3-thiadiazol- 344 methylphenoxy 5-yl 3-fluoro-5-1-methyl-3-(2-(2- 382 methylphenoxy methyl)propyl)pyrazol-5-yl3-fluoro-5- 3-chlorobenzo[b]thiophen- 413 methylphenoxy 2-yl 3-fluoro-5-4-chlorophenyl 357 methylphenoxy 3-fluoro-5- 4-methyl-2-phenyl-1,2,3-403 methylphenoxy triazol-5-yl 3-fluoro-5- benzo[b]thiophen-2-yl 378methylphenoxy 3-fluoro-5- 3,4-dimethylphenyl 350 methylphenoxy3-fluoro-5- 2-(phenoxy)pyridin-3-yl 415 methylphenoxy 3-fluoro-5-2-(methylthio)pyridin-3-yl 369 methylphenoxy 3-fluoro-5-5-methyl-3-phenylisoxazol- 403 methylphenoxy 4-yl 3-fluoro-5-4-chloro-1,3-dimethyl 426 methylphenoxy pyrazolo[3,4-b]pyridin-3- yl3-fluoro-5- 2-chloro-6-methylpyridin- 372 methylphenoxy 4-yl 3-fluoro-5-3,5-dimethylisoxazol-4-yl 341 methylphenoxy 3-fluoro-5- 1-naphthyl 372methylphenoxy 3-fluoro-5- 2-fluorophenyl 340 methylphenoxy 3-fluoro-5-4-propylphenyl 364 methylphenoxy 3-fluoro-5- 4-(trifluoromethyl)phenyl390 methylphenoxy 3-fluoro-5- 3-fluorophenyl 340 methylphenoxy3-fluoro-5- 2,6-difluorophenyl 358 methylphenoxy 3-fluoro-5-2-chlorophenyl 357 methylphenoxy 3-fluoro-5- 3-(chloromethyl)phenyl 371methylphenoxy 3-fluoro-5- 4-(2-(2- 378 methylphenoxymethyl)propyl)phenyl 3-fluoro-5- 3-chlorophenyl 357 methylphenoxy3-fluoro-5- 2-nitrophenyl 367 methylphenoxy 3-fluoro-5-3,5-dimethoxyphenyl 382 methylphenoxy 3-fluoro-5- 2,6-dichlorophenyl 391methylphenoxy 3-fluoro-5- 2,4-dichlorophenyl 391 methylphenoxy3-fluoro-5- 4-fluorophenyl 340 methylphenoxy 3-fluoro-5- 4-butylphenyl378 methylphenoxy 3-fluoro-5- 2-methylphenyl 336 methylphenoxy3-fluoro-5- phenyl 322 methylphenoxy 3-fluoro-5- 4-ethylphenyl 350methylphenoxy 3-fluoro-5- 2,3-difluorophenyl 358 methylphenoxy3-fluoro-5- 2,6-dimethoxyphenyl 382 methylphenoxy 3-fluoro-5-3,4-difluorophenyl 358 methylphenoxy 3-fluoro-5- 2,5-difluorophenyl 358methylphenoxy 3-fluoro-5- 4-ethoxyphenyl 366 methylphenoxy 3-fluoro-5-2,4,6-trichlorophenyl 426 methylphenoxy 3-fluoro-5- 3-methylphenyl 336methylphenoxy 3-fluoro-5- 2-fluoro-5- 408 methylphenoxy(trifluoromethyl)phenyl 3-fluoro-5- 3-methoxyphenyl 352 methylphenoxy3-fluoro-5- thien-2-yl 328 methylphenoxy 3-fluoro-5- 2-bromophenyl 401methylphenoxy 3-fluoro-5- 4-bromophenyl 401 methylphenoxy 3-fluoro-5-4-fluoro-3- 408 methylphenoxy (trifluoromethyl)phenyl 3-fluoro-5-3-(trifluoromethoxy)phenyl 406 methylphenoxy 3-fluoro-5-9-fluorenon-4-yl 424 methylphenoxy 3-fluoro-5- isoxazol-5-yl 313methylphenoxy 3-fluoro-5- benzofuroxan-5-yl 380 methylphenoxy3-fluoro-5- 2-chloropyrid-3-yl 358 methylphenoxy 3-fluoro-5-3,5-difluorophenyl 358 methylphenoxy 3-fluoro-5- 2-(4- 429 methylphenoxymethylphenoxy)pyridin-3-yl 3-fluoro-5- pyridin-4-yl 323 methylphenoxy3-fluoro-5- anthraquinon-2-yl 452 methylphenoxy 3-fluoro-5- 2-iodophenyl448 methylphenoxy 2-methylpyrid-3-yloxy 4-biphenyl 3812-methylpyrid-3-yloxy 3,4-dimethoxyphenyl 365 2-methylpyrid-3-yloxy2-(trifluoromethyl)phenyl 373 2-methylpyrid-3-yloxy 2,4-difluorophenyl341 2-methylpyrid-3-yloxy 4-cyanophenyl 330 2-methylpyrid-3-yloxy3-(trifluoromethyl)phenyl 373 2-methylpyrid-3-yloxy 3-cyanophenyl 3302-methylpyrid-3-yloxy 2-naphthyl 355 2-methylpyrid-3-yloxy2-methoxyphenyl 335 2-methylpyrid-3-yloxy 3,4,5-trimethylphenyl 3952-methylpyrid-3-yloxy 4-nitrophenyl 350 2-methylpyrid-3-yloxy3,4-dichlorophenyl 374 2-methylpyrid-3-yloxy 5-nitrofuran-2-yl 3402-methylpyrid-3-yloxy 3-bromophenyl 384 2-methylpyrid-3-yloxy 3-pyridyl306 2-methylpyrid-3-yloxy 2-ethoxynaphth-1-yl 399 2-methylpyrid-3-yloxy2,3-dichlorophenyl 374 2-methylpyrid-3-yloxy 3-nitrophenyl 3502-methylpyrid-3-yloxy 6-chloropyrid-3-yl 341 2-methylpyrid-3-yloxy4-(trifluoromethoxy)phenyl 389 2-methylpyrid-3-yloxy 2-fluoro-4- 391(trifluoromethyl)phenyl 2-methylpyrid-3-yloxy 3-bromothienyl 3902-methylpyrid-3-yloxy 2-acetoxyphenyl 363 2-methylpyrid-3-yloxy5-methylisoxazol-3-yl 310 2-methylpyrid-3-yloxy 2-(phenylthio)pyrid-3-yl414 2-methylpyrid-3-yloxy 2-(trifluoromethoxy)phenyl 3892-methylpyrid-3-yloxy 1-phenyl-5-propylpyrazin- 413 4-yl2-methylpyrid-3-yloxy 2-ethoxyphenyl 349 2-methylpyrid-3-yloxy3-chlorothien-2-yl 346 2-methylpyrid-3-yloxy 1-(2-(2-methyl)propyl)-3-365 methylpyrazol-5-yl 2-methylpyrid-3-yloxy 3,5-dichlorophenyl 3742-methylpyrid-3-yloxy 2-(propylthio)pyridin-3-yl 3802-methylpyrid-3-yloxy 2-(ethylthio)pyridin-3-yl 3662-methylpyrid-3-yloxy 3-bromopyridin-5-yl 385 2-methylpyrid-3-yloxy4-methyl-1,2,3-thiadiazol- 327 5-yl 2-methylpyrid-3-yloxy1-methyl-3-(2-(2- 365 methyl)propyl)pyrazol-5-yl 2-methylpyrid-3-yloxy3-chlorobenzo[b]thiophen- 396 2-yl 2-methylpyrid-3-yloxy 4-chlorophenyl340 2-methylpyrid-3-yloxy 4-methyl-2-phenyl-1,2,3- 386 triazol-5-yl2-methylpyrid-3-yloxy benzo[b]thiophen-2-yl 361 2-methylpyrid-3-yloxy3,4-dimethylphenyl 333 2-methylpyrid-3-yloxy 2-(phenoxy)pyridin-3-yl 3982-methylpyrid-3-yloxy 2-(methylthio)pyridin-3-yl 3522-methylpyrid-3-yloxy 5-methyl-3-phenylisoxazol- 386 4-yl2-methylpyrid-3-yloxy 4-chloro-1,3-dimethyl 409 pyrazolo[3,4-b]pyridin-3- yl 2-methylpyrid-3-yloxy 2-chloro-6-methylpyridin- 3554-yl 2-methylpyrid-3-yloxy 3,5-dimethylisoxazol-4-yl 3242-methylpyrid-3-yloxy 1-naphthyl 355 2-methylpyrid-3-yloxy2-fluorophenyl 323 2-methylpyrid-3-yloxy 4-propylphenyl 3472-methylpyrid-3-yloxy 4-(trifluoromethyl)phenyl 3732-methylpyrid-3-yloxy 3-fluorophenyl 323 2-methylpyrid-3-yloxy2,6-difluorophenyl 341 2-methylpyrid-3-yloxy 2-chlorophenyl 3402-methylpyrid-3-yloxy 3-(chloromethyl)phenyl 354 2-methylpyrid-3-yloxy4-(2-(2- 361 methyl)propyl)phenyl 2-methylpyrid-3-yloxy 3-chlorophenyl340 2-methylpyrid-3-yloxy 2-nitrophenyl 350 2-methylpyrid-3-yloxy3,5-dimethoxyphenyl 365 2-methylpyrid-3-yloxy 2,6-dichlorophenyl 3742-methylpyrid-3-yloxy 2,4-dichlorophenyl 374 2-methylpyrid-3-yloxy4-fluorophenyl 323 2-methylpyrid-3-yloxy 4-butylphenyl 3612-methylpyrid-3-yloxy 2-methylphenyl 319 2-methylpyrid-3-yloxy phenyl305 2-methylpyrid-3-yloxy 4-ethylphenyl 333 2-methylpyrid-3-yloxy2,3-difluorophenyl 341 2-methylpyrid-3-yloxy 2,6-dimethoxyphenyl 3652-methylpyrid-3-yloxy 3,4-difluorophenyl 341 2-methylpyrid-3-yloxy2,5-difluorophenyl 341 2-methylpyrid-3-yloxy 4-ethoxyphenyl 3492-methylpyrid-3-yloxy 2,4,6-trichlorophenyl 409 2-methylpyrid-3-yloxy3-methylphenyl 319 2-methylpyrid-3-yloxy 2-fluoro-5- 391(trifluoromethyl)phenyl 2-methylpyrid-3-yloxy 3-methoxyphenyl 3352-methylpyrid-3-yloxy thien-2-yl 311 2-methylpyrid-3-yloxy 2-bromophenyl384 2-methylpyrid-3-yloxy 4-bromophenyl 384 2-methylpyrid-3-yloxy4-fluoro-3- 391 (trifluoromethyl)phenyl 2-methylpyrid-3-yloxy3-(trifluoromethoxy)phenyl 389 2-methylpyrid-3-yloxy 9-fluorenon-4-yl407 2-methylpyrid-3-yloxy isoxazol-5-yl 296 2-methylpyrid-3-yloxybenzofuroxan-5-yl 363 2-methylpyrid-3-yloxy 2-chloropyrid-3-yl 3412-methylpyrid-3-yloxy 3,5-difluorophenyl 341 2-methylpyrid-3-yloxy 2-(4-412 methylphenoxy)pyridin-3-yl 2-methylpyrid-3-yloxy pyridin-4-yl 3062-methylpyrid-3-yloxy anthraquinon-2-yl 435 2-methylpyrid-3-yloxy2-iodophenyl 431 4-chloro-2,5- 3,4-dimethoxyphenyl 413 dimethylphenoxy4-chloro-2,5- 2-(trifluoromethyl)phenyl 421 dimethylphenoxy4-chloro-2,5- 2,4-difluorophenyl 389 dimethylphenoxy 4-chloro-2,5-3-(trifluoromethyl)phenyl 421 dimethylphenoxy 4-chloro-2,5- 2-naphthyl403 dimethylphenoxy 4-chloro-2,5- 2-methoxyphenyl 484 dimethylphenoxy4-chloro-2,5- 3,4,5-trimethylphenyl 443 dimethylphenoxy 4-chloro-2,5-3,4-dichlorophenyl 422 dimethylphenoxy 4-chloro-2,5- 3-bromophenyl 432dimethylphenoxy 4-chloro-2,5- 3-pyridyl 354 dimethylphenoxy4-chloro-2,5- 2-ethoxynaphth-1-yl 447 dimethylphenoxy 4-chloro-2,5-2,3-dichlorophenyl 422 dimethylphenoxy 4-chloro-2,5- 6-chloropyrid-3-yl388 dimethylphenoxy 4-chloro-2,5- 4-(trifluoromethoxy)phenyl 437dimethylphenoxy 4-chloro-2,5- 2-fluoro-4- 439 dimethylphenoxy(trifluoromethyl)phenyl 4-chloro-2,5- 3-bromothienyl 438 dimethylphenoxy4-chloro-2,5- 2-acetoxyphenyl 411 dimethylphenoxy 4-chloro-2,5-5-methylisoxazol-3-yl 358 dimethylphenoxy 4-chloro-2,5-2-(phenylthio)pyrid-3-yl 462 dimethylphenoxy 4-chloro-2,5-2-(trifluoromethoxy)phenyl 437 dimethylphenoxy 4-chloro-2,5-1-phenyl-5-propylpyrazin- 461 dimethylphenoxy 4-yl 4-chloro-2,5-2-ethoxyphenyl 397 dimethylphenoxy 4-chloro-2,5- 3-chlorothien-2-yl 393dimethylphenoxy 4-chloro-2,5- 1-(2-(2-methyl)propyl)-3- 413dimethylphenoxy methylpyrazol-5-yl 4-chloro-2,5- 3,5-dichlorophenyl 422dimethylphenoxy 4-chloro-2,5- 2-(propylthio)pyridin-3-yl 428dimethylphenoxy 4-chloro-2,5- 2-(ethylthio)pyridin-3-yl 414dimethylphenoxy 4-chloro-2,5- 3-bromopyridin-5-yl 433 dimethylphenoxy4-chloro-2,5- 4-methyl-1,2,3-thiadiazol- 375 dimethylphenoxy 5-yl4-chloro-2,5- 1-methyl-3-(2-(2- 413 dimethylphenoxymethyl)propyl)pyrazol-5-yl 4-chloro-2,5- 3-chlorobenzo[b]thiophen- 443dimethylphenoxy 2-yl 4-chloro-2,5- 4-chlorophenyl 387 dimethylphenoxy4-chloro-2,5- 4-methyl-2-phenyl-1,2,3- 434 dimethylphenoxy triazol-5-yl4-chloro-2,5- benzo[b]thiophen-2-yl 409 dimethylphenoxy 4-chloro-2,5-3,4-dimethylphenyl 381 dimethylphenoxy 4-chloro-2,5-2-(phenoxy)pyridin-3-yl 446 dimethylphenoxy 4-chloro-2,5-2-(methylthio)pyridin-3-yl 400 dimethylphenoxy 4-chloro-2,5-5-methyl-3-phenylisoxazol- 434 dimethylphenoxy 4-yl 4-chloro-2,5-4-chloro-1,3-dimethyl 456 dimethylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-2,5- 2-chloro-6-methylpyridin- 402 dimethylphenoxy 4-yl4-chloro-2,5- 3,5-dimethylisoxazol-4-yl 372 dimethylphenoxy4-chloro-2,5- 1-naphthyl 403 dimethylphenoxy 4-chloro-2,5-2-fluorophenyl 371 dimethylphenoxy 4-chloro-2,5- 4-propylphenyl 395dimethylphenoxy 4-chloro-2,5- 3-fluorophenyl 371 dimethylphenoxy4-chloro-2,5- 2,6-difluorophenyl 389 dimethylphenoxy 4-chloro-2,5-2-chlorophenyl 387 dimethylphenoxy 4-chloro-2,5- 3-(chloromethyl)phenyl401 dimethylphenoxy 4-chloro-2,5- 4-(2-(2- 409 dimethylphenoxymethyl)propyl)phenyl 4-chloro-2,5- 3-chlorophenyl 387 dimethylphenoxy4-chloro-2,5- 3,5-dimethoxyphenyl 413 dimethylphenoxy 4-chloro-2,5-2,6-dichlorophenyl 422 dimethylphenoxy 4-chloro-2,5- 2,4-dichlorophenyl422 dimethylphenoxy 4-chloro-2,5- 4-fluorophenyl 371 dimethylphenoxy4-chloro-2,5- 4-butylphenyl 409 dimethylphenoxy 4-chloro-2,5-2-methylphenyl 367 dimethylphenoxy 4-chloro-2,5- phenyl 353dimethylphenoxy 4-chloro-2,5- 4-ethylphenyl 381 dimethylphenoxy4-chloro-2,5- 2,3-difluorophenyl 389 dimethylphenoxy 4-chloro-2,5-2,6-dimethoxyphenyl 413 dimethylphenoxy 4-chloro-2,5- 3,4-difluorophenyl389 dimethylphenoxy 4-chloro-2,5- 2,5-difluorophenyl 389 dimethylphenoxy4-chloro-2,5- 4-ethoxyphenyl 397 dimethylphenoxy 4-chloro-2,5-2,4,6-trichlorophenyl 456 dimethylphenoxy 4-chloro-2,5- 3-methylphenyl367 dimethylphenoxy 4-chloro-2,5- 2-fluoro-5- 439 dimethylphenoxy(trifluoromethyl)phenyl 4-chloro-2,5- 3-methoxyphenyl 383dimethylphenoxy 4-chloro-2,5- 2-bromophenyl 432 dimethylphenoxy4-chloro-2,5- 4-bromophenyl 432 dimethylphenoxy 4-chloro-2,5-4-fluoro-3- 439 dimethylphenoxy (trifluoromethyl)phenyl 4-chloro-2,5-3-(trifluoromethoxy)phenyl 437 dimethylphenoxy 4-chloro-2,5-9-fluorenon-4-yl 455 dimethylphenoxy 4-chloro-2,5- isoxazol-5-yl 344dimethylphenoxy 4-chloro-2,5- benzofuroxan-5-yl 411 dimethylphenoxy4-chloro-2,5- 2-chloropyrid-3-yl 388 dimethylphenoxy 4-chloro-2,5- 2-(4-460 dimethylphenoxy methylphenoxy)pyridin-3-yl 4-chloro-2,5-pyridin-4-yl 354 dimethylphenoxy 4-chloro-2,5- anthraquinon-2-yl 483dimethylphenoxy 4-chloro-2,5- 2-iodophenyl 479 dimethylphenoxy4-chloro-2,5- 4-pentylphenyl 423 dimethylphenoxy 4-chloro-2,5-2-(4-chlorophenylthio) 496 dimethylphenoxy pyridin-3-yl 4-chloro-2,5-2,6-dimethylphenyl 381 dimethylphenoxy 4-chloro-2,5- 2,5-dimethoxyphenyl413 dimethylphenoxy 4-chloro-2,5- 2,5-dichloropyridin-3-yl 423dimethylphenoxy 4-chloro-2,5- 2-chloro-6-methoxypyridin- 418dimethylphenoxy 4-yl 4-chloro-2,5- 2,3-dichloropyridin-5-yl 423dimethylphenoxy 4-chloro-2,5- 1-naphthyl 417 dimethylphenoxy4-chloro-2,5- 2,4-dimethoxyphenyl 413 dimethylphenoxy 4-chloro-2,5-3,5-bis(trifluoromethyl) 489 dimethylphenoxy phenyl 4-chloro-2,5- 2-(4-480 dimethylphenoxy chlorophenoxy)pyridin-3-yl 4-chloro-2,5-pentafluorophenyl 443 dimethylphenoxy 4-methoxyphenoxy3,4-dimethoxyphenyl 380 4-methoxyphenoxy 2-(trifluoromethyl)phenyl 3884-methoxyphenoxy 2,4-difluorophenyl 356 4-methoxyphenoxy3-(trifluoromethyl)phenyl 388 4-methoxyphenoxy 2-naphthyl 3704-methoxyphenoxy 2-methoxyphenyl 350 4-methoxyphenoxy3,4,5-trimethylphenyl 410 4-methoxyphenoxy 3,4-dichlorophenyl 3894-methoxyphenoxy 3-bromophenyl 399 4-methoxyphenoxy 3-pyridyl 3214-methoxyphenoxy 2-ethoxynaphth-1-yl 414 4-methoxyphenoxy2,3-dichlorophenyl 389 4-methoxyphenoxy 6-chloropyrid-3-yl 3564-methoxyphenoxy 4-(trifluoromethoxy)phenyl 404 4-methoxyphenoxy2-fluoro-4- 406 (trifluoromethyl)phenyl 4-methoxyphenoxy 3-bromothienyl405 4-methoxyphenoxy 2-acetoxyphenyl 378 4-methoxyphenoxy5-methylisoxazol-3-yl 325 4-methoxyphenoxy 2-(phenylthio)pyrid-3-yl 4294-methoxyphenoxy 2-(trifluoromethoxy)phenyl 404 4-methoxyphenoxy1-phenyl-5-propylpyrazin- 428 4-yl 4-methoxyphenoxy 2-ethoxyphenyl 3644-methoxyphenoxy 3-chlorothien-2-yl 361 4-methoxyphenoxy1-(2-(2-methyl)propyl)-3- 380 methylpyrazol-5-yl 4-methoxyphenoxy3,5-dichlorophenyl 389 4-methoxyphenoxy 2-(propylthio)pyridin-3-yl 3954-methoxyphenoxy 2-(ethylthio)pyridin-3-yl 381 4-methoxyphenoxy3-bromopyridin-5-yl 400 4-methoxyphenoxy 4-methyl-1,2,3-thiadiazol- 3425-yl 4-methoxyphenoxy 1-methyl-3-(2-(2- 380 methyl)propyl)pyrazol-5-yl4-methoxyphenoxy 3-chlorobenzo[b]thiophen- 411 2-yl 4-methoxyphenoxy4-chlorophenyl 355 4-methoxyphenoxy 4-methyl-2-phenyl-1,2,3- 401triazol-5-yl 4-methoxyphenoxy benzo[b]thiophen-2-yl 376 4-methoxyphenoxy3,4-dimethylphenyl 348 4-methoxyphenoxy 2-(phenoxy)pyridin-3-yl 4134-methoxyphenoxy 2-(methylthio)pyridin-3-yl 367 4-methoxyphenoxy5-methyl-3-phenylisoxazol- 401 4-yl 4-methoxyphenoxy4-chloro-1,3-dimethyl 424 pyrazolo[3,4-b]pyridin-3- yl 4-methoxyphenoxy2-chloro-6-methylpyridin- 370 4-yl 4-methoxyphenoxy3,5-dimethylisoxazol-4-yl 339 4-methoxyphenoxy 1-naphthyl 3704-methoxyphenoxy 2-fluorophenyl 338 4-methoxyphenoxy 4-propylphenyl 3624-methoxyphenoxy 3-fluorophenyl 338 4-methoxyphenoxy 2,6-difluorophenyl356 4-methoxyphenoxy 2-chlorophenyl 355 4-methoxyphenoxy3-(chloromethyl)phenyl 369 4-methoxyphenoxy 4-(2-(2- 376methyl)propyl)phenyl 4-methoxyphenoxy 3-chlorophenyl 3554-methoxyphenoxy 3,5-dimethoxyphenyl 380 4-methoxyphenoxy2,6-dichlorophenyl 389 4-methoxyphenoxy 2,4-dichlorophenyl 3894-methoxyphenoxy 4-fluorophenyl 338 4-methoxyphenoxy 4-butylphenyl 3764-methoxyphenoxy 2-methylphenyl 334 4-methoxyphenoxy phenyl 3204-methoxyphenoxy 4-ethylphenyl 348 4-methoxyphenoxy 2,3-difluorophenyl356 4-methoxyphenoxy 2,6-dimethoxyphenyl 380 4-methoxyphenoxy3,4-difluorophenyl 356 4-methoxyphenoxy 2,5-difluorophenyl 3564-methoxyphenoxy 4-ethoxyphenyl 364 4-methoxyphenoxy2,4,6-trichlorophenyl 424 4-methoxyphenoxy 3-methylphenyl 3344-methoxyphenoxy 2-fluoro-5- 406 (trifluoromethyl)phenyl4-methoxyphenoxy 3-methoxyphenyl 350 4-methoxyphenoxy 2-bromophenyl 3994-methoxyphenoxy 4-bromophenyl 399 4-methoxyphenoxy 4-fluoro-3- 406(trifluoromethyl)phenyl 4-methoxyphenoxy 3-(trifluoromethoxy)phenyl 4044-methoxyphenoxy 9-fluorenon-4-yl 422 4-methoxyphenoxy isoxazol-5-yl 3114-methoxyphenoxy benzofuroxan-5-yl 378 4-methoxyphenoxy2-chloropyrid-3-yl 356 4-methoxyphenoxy 2-(4- 427methylphenoxy)pyridin-3-yl 4-methoxyphenoxy pyridin-4-yl 3214-methoxyphenoxy anthraquinon-2-yl 450 4-methoxyphenoxy 2-iodophenyl 4464-methoxyphenoxy 4-pentylphenyl 390 4-methoxyphenoxy2-(4-chlorophenylthio) 464 pyridin-3-yl 4-methoxyphenoxy2,6-dimethylphenyl 348 4-methoxyphenoxy 2,5-dimethoxyphenyl 3804-methoxyphenoxy 2,5-dichloropyridin-3-yl 390 4-methoxyphenoxy2-chloro-6-methoxypyridin- 386 4-yl 4-methoxyphenoxy2,3-dichloropyridin-5-yl 390 4-methoxyphenoxy 1-naphthyl 3844-methoxyphenoxy 2,4-dimethoxyphenyl 380 4-methoxyphenoxy 3,5-bis(trifluoromethyl) 456 phenyl 4-methoxyphenoxy 2-(4- 448chlorophenoxy)pyridin-3-yl 4-methoxyphenoxy pentafluorophenyl 4102-(2-propoxy)phenoxy 3,4-dimethoxyphenyl 408 2-(2-propoxy)phenoxy2-(trifluoromethyl)phenyl 416 2-(2-propoxy)phenoxy 2,4-difluorophenyl384 2-(2-propoxy)phenoxy 3-(trifluoromethyl)phenyl 4162-(2-propoxy)phenoxy 2-naphthyl 398 2-(2-propoxy)phenoxy 2-methoxyphenyl378 2-(2-propoxy)phenoxy 3,4,5-trimethylphenyl 438 2-(2-propoxy)phenoxy3,4-dichlorophenyl 417 2-(2-propoxy)phenoxy 3-bromophenyl 4272-(2-propoxy)phenoxy 3-pyridyl 349 2-(2-propoxy)phenoxy2-ethoxynaphth-1-yl 442 2-(2-propoxy)phenoxy 2,3-dichlorophenyl 4172-(2-propoxy)phenoxy 6-chloropyrid-3-yl 384 2-(2-propoxy)phenoxy4-(trifluoromethoxy)phenyl 432 2-(2-propoxy)phenoxy 2-fluoro-4- 434(trifluoromethyl)phenyl 2-(2-propoxy)phenoxy 3-bromothienyl 4332-(2-propoxy)phenoxy 2-acetoxyphenyl 406 2-(2-propoxy)phenoxy5-methylisoxazol-3-yl 353 2-(2-propoxy)phenoxy 2-(phenylthio)pyrid-3-yl458 2-(2-propoxy)phenoxy 2-(trifluoromethoxy)phenyl 4322-(2-propoxy)phenoxy 1-phenyl-5-propylpyrazin- 457 4-yl2-(2-propoxy)phenoxy 2-ethoxyphenyl 392 2-(2-propoxy)phenoxy3-chlorothien-2-yl 389 2-(2-propoxy)phenoxy 1-(2-(2-methyl)propyl)-3-408 methylpyrazol-5-yl 2-(2-propoxy)phenoxy 3,5-dichlorophenyl 4172-(2-propoxy)phenoxy 2-(propylthio)pyridin-3-yl 423 2-(2-propoxy)phenoxy2-(ethylthio)pyridin-3-yl 409 2-(2-propoxy)phenoxy 3-bromopyridin-5-yl428 2-(2-propoxy)phenoxy 4-methyl-1,2,3-thiadiazol- 370 5-yl2-(2-propoxy)phenoxy 1-methyl-3-(2-(2- 408 methyl)propyl)pyrazol-5-yl2-(2-propoxy)phenoxy 3-chlorobenzo[b]thiophen- 439 2-yl2-(2-propoxy)phenoxy 4-chlorophenyl 383 2-(2-propoxy)phenoxy4-methyl-2-phenyl-1,2,3- 429 triazol-5-yl 2-(2-propoxy)phenoxybenzo[b]thiophen-2-yl 404 2-(2-propoxy)phenoxy 3,4-dimethylphenyl 3762-(2-propoxy)phenoxy 2-(phenoxy)pyridin-3-yl 441 2-(2-propoxy)phenoxy2-(methylthio)pyridin-3-yl 395 2-(2-propoxy)phenoxy5-methyl-3-phenylisoxazol- 429 4-yl 2-(2-propoxy)phenoxy4-chloro-1,3-dimethyl 452 pyrazolo[3,4-b]pyridin-3- yl2-(2-propoxy)phenoxy 2-chloro-6-methylpyridin- 398 4-yl2-(2-propoxy)phenoxy 3,5-dimethylisoxazol-4-yl 367 2-(2-propoxy)phenoxy1-naphthyl 398 2-(2-propoxy)phenoxy 2-fluorophenyl 3662-(2-propoxy)phenoxy 4-propylphenyl 390 2-(2-propoxy)phenoxy3-fluorophenyl 366 2-(2-propoxy)phenoxy 2,6-difluorophenyl 3842-(2-propoxy)phenoxy 2-chlorophenyl 383 2-(2-propoxy)phenoxy3-(chloromethyl)phenyl 397 2-(2-propoxy)phenoxy 4-(2-(2- 404methyl)propyl)phenyl 2-(2-propoxy)phenoxy 3-chlorophenyl 3832-(2-propoxy)phenoxy 3,5-dimethoxyphenyl 408 2-(2-propoxy)phenoxy2,6-dichlorophenyl 417 2-(2-propoxy)phenoxy 2,4-dichlorophenyl 4172-(2-propoxy)phenoxy 4-fluorophenyl 366 2-(2-propoxy)phenoxy4-butylphenyl 404 2-(2-propoxy)phenoxy 2-methylphenyl 3622-(2-propoxy)phenoxy phenyl 348 2-(2-propoxy)phenoxy 4-ethylphenyl 3762-(2-propoxy)phenoxy 2,3-difluorophenyl 384 2-(2-propoxy)phenoxy2,6-dimethoxyphenyl 408 2-(2-propoxy)phenoxy 3,4-difluorophenyl 3842-(2-propoxy)phenoxy 2,5-difluorophenyl 384 2-(2-propoxy)phenoxy4-ethoxyphenyl 392 2-(2-propoxy)phenoxy 2,4,6-trichlorophenyl 4522-(2-propoxy)phenoxy 3-methylphenyl 362 2-(2-propoxy)phenoxy 2-fluoro-5-434 (trifluoromethyl)phenyl 2-(2-propoxy)phenoxy 3-methoxyphenyl 3782-(2-propoxy)phenoxy 2-bromophenyl 427 2-(2-propoxy)phenoxy4-bromophenyl 427 2-(2-propoxy)phenoxy 4-fluoro-3- 434(trifluoromethyl)phenyl 2-(2-propoxy)phenoxy 3-(trifluoromethoxy)phenyl432 2-(2-propoxy)phenoxy 9-fluorenon-4-yl 450 2-(2-propoxy)phenoxyisoxazol-5-yl 339 2-(2-propoxy)phenoxy benzofuroxan-5-yl 4062-(2-propoxy)phenoxy 2-chloropyrid-3-yl 384 2-(2-propoxy)phenoxy 2-(4-455 methylphenoxy)pyridin-3-yl 2-(2-propoxy)phenoxy pyridin-4-yl 3492-(2-propoxy)phenoxy anthraquinon-2-yl 478 2-(2-propoxy)phenoxy2-iodophenyl 474 2-(2-propoxy)phenoxy 4-pentylphenyl 4192-(2-propoxy)phenoxy 2-(4-chlorophenylthio) 492 pyridin-3-yl2-(2-propoxy)phenoxy 2,6-dimethylphenyl 376 2-(2-propoxy)phenoxy2,5-dimethoxyphenyl 408 2-(2-propoxy)phenoxy 2,5-dichloropyridin-3-yl418 2-(2-propoxy)phenoxy 2-chloro-6-methoxypyridin- 414 4-yl2-(2-propoxy)phenoxy 2,3-dichloropyridin-5-yl 418 2-(2-propoxy)phenoxy1-naphthyl 412 2-(2-propoxy)phenoxy 2,4-dimethoxyphenyl 4082-(2-propoxy)phenoxy 3,5-bis (trifluoromethyl) 484 phenyl2-(2-propoxy)phenoxy 2-(4- 476 chlorophenoxy)pyridin-3-yl2-(2-propoxy)phenoxy pentafluorophenyl 438 4-fluorophenoxy3,4-dimethoxyphenyl 368 4-fluorophenoxy 2-(trifluoromethyl)phenyl 3764-fluorophenoxy 2,4-difluorophenyl 344 4-fluorophenoxy3-(trifluoromethyl)phenyl 376 4-fluorophenoxy 2-naphthyl 3584-fluorophenoxy 2-methoxyphenyl 338 4-fluorophenoxy3,4,5-trimethylphenyl 398 4-fluorophenoxy 3,4-dichlorophenyl 3774-fluorophenoxy 3-bromophenyl 387 4-fluorophenoxy 3-pyridyl 3094-fluorophenoxy 2-ethoxynaphth-1-yl 402 4-fluorophenoxy2,3-dichlorophenyl 377 4-fluorophenoxy 6-chloropyrid-3-yl 3444-fluorophenoxy 4-(trifluoromethoxy)phenyl 392 4-fluorophenoxy2-fluoro-4- 394 (trifluoromethyl)phenyl 4-fluorophenoxy 3-bromothienyl393 4-fluorophenoxy 2-acetoxyphenyl 366 4-fluorophenoxy5-methylisoxazol-3-yl 313 4-fluorophenoxy 2-(phenylthio)pyrid-3-yl 4174-fluorophenoxy 2-(trifluoromethoxy)phenyl 392 4-fluorophenoxy1-phenyl-5-propylpyrazin- 416 4-yl 4-fluorophenoxy 2-ethoxyphenyl 3524-fluorophenoxy 3-chlorothien-2-yl 349 4-fluorophenoxy1-(2-(2-methyl)propyl)-3- 368 methylpyrazol-5-yl 4-fluorophenoxy3,5-dichlorophenyl 377 4-fluorophenoxy 2-(propylthio)pyridin-3-yl 3834-fluorophenoxy 2-(ethylthio)pyridin-3-yl 369 4-fluorophenoxy3-bromopyridin-5-yl 388 4-fluorophenoxy 4-methyl-1,2,3-thiadiazol- 3305-yl 4-fluorophenoxy 1-methyl-3-(2-(2- 368 methyl)propyl)pyrazol-5-yl4-fluorophenoxy 3-chlorobenzo[b]thiophen- 399 2-yl 4-fluorophenoxy4-chlorophenyl 343 4-fluorophenoxy 4-methyl-2-phenyl-l,2,3- 389triazol-5-yl 4-fluorophenoxy benzo[b]thiophen-2-yl 364 4-fluorophenoxy3,4-dimethylphenyl 336 4-fluorophenoxy 2-(phenoxy)pyridin-3-yl 4014-fluorophenoxy 2-(methylthio)pyridin-3-yl 355 4-fluorophenoxy5-methyl-3-phenylisoxazol- 389 4-yl 4-fluorophenoxy4-chloro-1,3-dimethyl 412 pyrazolo[3,4-b]pyridin-3- yl 4-fluorophenoxy2-chloro-6-methylpyridin- 358 4-yl 4-fluorophenoxy3,5-dimethylisoxazol-4-yl 327 4-fluorophenoxy 1-naphthyl 3584-fluorophenoxy 2-fluorophenyl 326 4-fluorophenoxy 4-propylphenyl 3504-fluorophenoxy 3-fluorophenyl 326 4-fluorophenoxy 2,6-difluorophenyl344 4-fluorophenoxy 2-chlorophenyl 343 4-fluorophenoxy3-(chloromethyl)phenyl 357 4-fluorophenoxy 4-(2-(2- 364methyl)propyl)phenyl 4-fluorophenoxy 3-chlorophenyl 343 4-fluorophenoxy3,5-dimethoxyphenyl 368 4-fluorophenoxy 2,6-dichlorophenyl 3774-fluorophenoxy 2,4-dichlorophenyl 377 4-fluorophenoxy 4-fluorophenyl326 4-fluorophenoxy 4-butylphenyl 364 4-fluorophenoxy 2-methylphenyl 3224-fluorophenoxy phenyl 308 4-fluorophenoxy 4-ethylphenyl 3364-fluorophenoxy 2,3-difluorophenyl 344 4-fluorophenoxy2,6-dimethoxyphenyl 368 4-fluorophenoxy 3,4-difluorophenyl 3444-fluorophenoxy 2,5-difluorophenyl 344 4-fluorophenoxy 4-ethoxyphenyl352 4-fluorophenoxy 2,4,6-trichlorophenyl 412 4-fluorophenoxy3-methylphenyl 322 4-fluorophenoxy 2-fluoro-5- 394(trifluoromethyl)phenyl 4-fluorophenoxy 3-methoxyphenyl 3384-fluorophenoxy 2-bromophenyl 387 4-fluorophenoxy 4-bromophenyl 3874-fluorophenoxy 4-fluoro-3- 394 (trifluoromethyl)phenyl 4-fluorophenoxy3-(trifluoromethoxy)phenyl 392 4-fluorophenoxy 9-fluorenon-4-yl 4104-fluorophenoxy isoxazol-5-yl 299 4-fluorophenoxy benzofuroxan-5-yl 3664-fluorophenoxy 2-chloropyrid-3-yl 344 4-fluorophenoxy 2-(4- 415methylphenoxy)pyridin-3-yl 4-fluorophenoxy pyridin-4-yl 3094-fluorophenoxy anthraquinon-:2-yl 438 4-fluorophenoxy 2-iodophenyl 4344-fluorophenoxy 4-pentylphenyl 378 4-fluorophenoxy2-(4-chlorophenylthio) 452 pyridin-3-yl 4-fluorophenoxy2,6-dimethylphenyl 336 4-fluorophenoxy 2,5-dimethoxyphenyl 3684-fluorophenoxy 2,5-dichloropyridin-3-yl 378 4-fluorophenoxy2-chloro-6-methoxypyridin- 374 4-yl 4-fluorophenoxy2,3-dichloropyridin-5-yl 378 4-fluorophenoxy 1-naphthyl 3724-fluorophenoxy 2,4-dimethoxyphenyl 368 4-fluorophenoxy 3,5- 444bis(trifluoromethyl)phenyl 4-fluorophenoxy 2-(4- 436chlorophenoxy)pyridin-3-yl 4-fluorophenoxy pentafluorophenyl 3984-chlorophenoxy 3,4-dimethoxyphenyl 385 4-chlorophenoxy2-(trifluoromethyl)phenyl 393 4-chlorophenoxy 2,4-difluorophenyl 3614-chlorophenoxy 3-(trifluoromethyl)phenyl 393 4-chlorophenoxy 2-naphthyl375 4-chlorophenoxy 2-methoxyphenyl 355 4-chlorophenoxy3,4,5-trimethylphenyl 415 4-chlorophenoxy 3,4-dichlorophenyl 3944-chlorophenoxy 3-bromophenyl 404 4-chlorophenoxy 3-pyridyl 3264-chlorophenoxy 2-ethoxynaphth-1-yl 419 4-chlorophenoxy2,3-dichlorophenyl 394 4-chlorophenoxy 6-chloropyrid-3-yl 3604-chlorophenoxy 4-(trifluoromethoxy)phenyl 409 4-chlorophenoxy2-fluoro-4- 411 (trifluoromethyl)phenyl 4-chlorophenoxy 3-bromothienyl410 4-chlorophenoxy 2-acetoxyphenyl 383 4-chlorophenoxy5-methylisoxazol-3-yl 330 4-chlorophenoxy 2-(phenylthio)pyrid-3-yl 4344-chlorophenoxy 2-(trifluoromethoxy)phenyl 409 4-chlorophenoxy1-phenyl-5-propylpyrazin- 433 4-yl 4-chlorophenoxy 2-ethoxyphenyl 3694-chlorophenoxy 3-chlorothien-2-yl 365 4-chlorophenoxy1-(2-(2-methyl)propyl)-3- 385 methylpyrazol-5-yl 4-chlorophenoxy3,5-dichlorophenyl 394 4-chlorophenoxy 2-(propylthio)pyridin-3-yl 4004-chlorophenoxy 2-(ethylthio)pyridin-3-yl 386 4-chlorophenoxy3-bromopyridin-5-yl 405 4-chlorophenoxy 4-methyl-1,2,3-thiadiazol- 3475-yl 4-chlorophenoxy 1-methyl-3-(2-(2- 385 methyl)propyl)pyrazol-5-yl4-chlorophenoxy 3-chlorobenzo[b]thiophen- 415 2-yl 4-chlorophenoxy4-chlorophenyl 359 4-chlorophenoxy 4-methyl-2-phenyl-1,2,3- 406triazol-5-yl 4-chlorophenoxy benzo[b]thiophen-2-yl 381 4-chlorophenoxy3,4-dimethylphenyl 353 4-chlorophenoxy 2-(phenoxy)pyridin-3-yl 4184-chlorophenoxy 2-(methylthio)pyridin-3-yl 372 4-chlorophenoxy5-methyl-3-phenylisoxazol- 406 4-yl 4-chlorophenoxy4-chloro-1,3-dimethyl 428 pyrazolo[3,4-b]pyridin-3- yl 4-chlorophenoxy2-chloro-6-methylpyridin- 374 4-yl 4-chlorophenoxy3,5-dimethylisoxazol-4-yl 344 4-chlorophenoxy 1-naphthyl 3754-chlorophenoxy 2-fluorophenyl 343 4-chlorophenoxy 4-propylphenyl 3674-chlorophenoxy 3-fluorophenyl 343 4-chlorophenoxy 2,6-difluorophenyl361 4-chlorophenoxy 2-chlorophenyl 359 4-chlorophenoxy3-(chloromethyl)phenyl 373 4-chlorophenoxy 4-(2-(2- 381methyl)propyl)phenyl 4-chlorophenoxy 3-chlorophenyl 359 4-chlorophenoxy3,5-dimethoxyphenyl 385 4-chlorophenoxy 2,6-dichlorophenyl 3944-chlorophenoxy 2,4-dichlorophenyl 394 4-chlorophenoxy 4-fluorophenyl343 4-chlorophenoxy 4-butylphenyl 381 4-chlorophenoxy 2-methylphenyl 3394-chlorophenoxy phenyl 325 4-chlorophenoxy 4-ethylphenyl 3534-chlorophenoxy 2,3-difluorophenyl 361 4-chlorophenoxy2,6-dimethoxyphenyl 385 4-chlorophenoxy 3,4-difluorophenyl 3614-chlorophenoxy 2,5-difluorophenyl 361 4-chlorophenoxy 4-ethoxyphenyl369 4-chlorophenoxy 2,4,6-trichlorophenyl 428 4-chlorophenoxy3-methylphenyl 339 4-chlorophenoxy 2-fluoro-5- 411(trifluoromethyl)phenyl 4-chlorophenoxy 3-methoxyphenyl 3554-chlorophenoxy 2-bromophenyl 404 4-chlorophenoxy 4-bromophenyl 4044-chlorophenoxy 4-fluoro-3- 411 (trifluoromethyl)phenyl 4-chlorophenoxy3-(trifluoromethoxy)phenyl 409 4-chlorophenoxy 9-fluorenon-4-yl 4274-chlorophenoxy isoxazol-5-yl 316 4-chlorophenoxy benzofuroxan-5-yl 3834-chlorophenoxy 2-chloropyrid-3-yl 360 4-chlorophenoxy 2-(4- 432methylphenoxy)pyridin-3-yl 4-chlorophenoxy pyridin-4-yl 3264-chlorophenoxy anthraquinon-2-yl 455 4-chlorophenoxy 2-iodophenyl 4514-chlorophenoxy 4-pentylphenyl 395 4-chlorophenoxy2-(4-chlorophenylthio) 468 pyridin-3-yl 4-chlorophenoxy2,6-dimethylphenyl 353 4-chlorophenoxy 2,5-dimethoxyphenyl 3854-chlorophenoxy 2,5-dichloropyridin-3-yl 395 4-chlorophenoxy2-chloro-6-methoxypyridin- 390 4-yl 4-chlorophenoxy2,3-dichloropyridin-5-yl 395 4-chlorophenoxy 1-naphthyl 3894-chlorophenoxy 2,4-dimethoxyphenyl 385 4-chlorophenoxy 3,5- 461 bis(trifluoromethyl)phenyl 4-chlorophenoxy 2-(4- 452chlorophenoxy)pyridin-3-yl 4-chlorophenoxy pentafluorophenyl 4152,4-difluorophenoxy 3,4-dimethoxyphenyl 386 2,4-difluorophenoxy2-(trifluoromethyl)phenyl 394 2,4-difluorophenoxy 2,4-difluorophenyl 3622,4-difluorophenoxy 3-(trifluoromethyl)phenyl 394 2,4-difluorophenoxy2-naphthyl 376 2,4-difluorophenoxy 2-methoxyphenyl 3562,4-difluorophenoxy 3,4,5-trimethylphenyl 416 2,4-difluorophenoxy3,4-dichlorophenyl 395 2,4-difluorophenoxy 3-bromophenyl 4052,4-difluorophenoxy 3-pyridyl 327 2,4-difluorophenoxy2-ethoxynaphth-1-yl 420 2,4-difluorophenoxy 2,3-dichlorophenyl 3952,4-difluorophenoxy 6-chloropyrid-3-yl 362 2,4-difluorophenoxy4-(trifluoromethoxy)phenyl 410 2,4-difluorophenoxy 2-fluoro-4- 412(trifluoromethyl)phenyl 2,4-difluorophenoxy 3-bromothienyl 4112,4-difluorophenoxy 2-acetoxyphenyl 384 2,4-difluorophenoxy5-methylisoxazol-3-yl 331 2,4-difluorophenoxy 2-(phenylthio)pyrid-3-yl435 2,4-difluorophenoxy 2-(trifluoromethoxy)phenyl 4102,4-difluorophenoxy 1-phenyl-5-propylpyrazin- 434 4-yl2,4-difluorophenoxy 2-ethoxyphenyl 370 2,4-difluorophenoxy3-chlorothien-2-yl 367 2,4-difluorophenoxy 1-(2-(2-methyl)propyl)-3- 386methylpyrazol-5-yl 2,4-difluorophenoxy 3,5-dichlorophenyl 3952,4-difluorophenoxy 2-(propylthio)pyridin-3-yl 401 2,4-difluorophenoxy2-(ethylthio)pyridin-3-yl 387 2,4-difluorophenoxy 3-bromopyridin-3-yl406 2,4-difluorophenoxy 4-methyl-1,2,3-thiadiazol- 348 5-yl2,4-difluorophenoxy 1-methyl-3-(2-(2- 386 methyl)propyl)pyrazol-5-yl2,4-difluorophenoxy 3-chlorobenzo[b]thiophen- 417 2-yl2,4-difluorophenoxy 4-chlorophenyl 361 2,4-difluorophenoxy4-methyl-2-phenyl-1,2,3- 407 triazol-5-yl 2,4-difluorophenoxybenzo[b]thiophen-2-yl 382 2,4-difluorophenoxy 3,4-dimethylphenyl 3542,4-difluorophenoxy 2-(phenoxy)pyridin-3-yl 409 2,4-difluorophenoxy2-(methylthio)pyridin-3-yl 373 2,4-difluorophenoxy5-methyl-3-phenylisoxazol- 407 4-yl 2,4-difluorophenoxy4-chloro-1,3-dimethyl 430 pyrazolo[3,4-b]pyridin-3- yl2,4-difluorophenoxy 2-chloro-6-methylpyridin- 376 4-yl2,4-difluorophenoxy 3,5-dimethylisoxazol-4-yl 345 2,4-difluorophenoxy1-naphthyl 376 2,4-difluorophenoxy 2-fluorophenyl 3442,4-difluorophenoxy 4-propylphenyl 363 2,4-difluorophenoxy3-fluorophenyl 344 2,4-difluorophenoxy 2,6-difluorophenyl 3622,4-difluorophenoxy 2-chlorophenyl 361 2,4-difluorophenoxy3-(chloromethyl)phenyl 375 2,4-difluorophenoxy 4-(2-(2- 382methyl)propyl)phenyl 2,4-difluorophenoxy 3-chlorophenyl 3612,4-difluorophenoxy 3,5-dimethoxyphenyl 386 2,4-difluorophenoxy2,6-dichlorophenyl 395 2,4-difluorophenoxy 2,4-dichlorophenyl 3922,4-difluorophenoxy 4-fluorophenyl 344 2,4-difluorophenoxy 4-butylphenyl382 2,4-difluorophenoxy 2-methylphenyl 340 2,4-difluorophenoxy phenyl326 2,4-difluorophenoxy 4-ethylphenyl 354 2,4-difluorophenoxy2,3-difluorophenyl 362 2,4-difluorophenoxy 2,6-dimethoxyphenyl 3862,4-difluorophenoxy 3,4-difluorophenyl 362 2,4-difluorophenoxy2,5-difluorophenyl 362 2,4-difluorophenoxy 4-ethoxyphenyl 3702,4-difluorophenoxy 2,4,6-trichlorophenyl 430 2,4-difluorophenoxy3-methylphenyl 340 2,4-difluorophenoxy 2-fluoro-5- 412(trifluoromethyl)phenyl 2,4-difluorophenoxy 3-methoxyphenyl 3562,4-difluorophenoxy 2-bromophenyl 405 2,4-difluorophenoxy 4-bromophenyl405 2,4-difluorophenoxy 4-fluoro-3- 412 (trifluoromethyl)phenyl2,4-difluorophenoxy 3-(trifluoromethoxy)phenyl 410 2,4-difluorophenoxy9-fluorenon-4-yl 428 2,4-difluorophenoxy isoxazol-5-yl 3172,4-difluorophenoxy benzofuroxan-5-yl 384 2,4-difluorophenoxy2-chloropyrid-3-yl 362 2,4-difluorophenoxy 2-(4- 433methylphenoxy)pyridin-3-yl 2,4-difluorophenoxy pyridin-4-yl 3272,4-difluorophenoxy anthraquinon-2-yl 456 2,4-difluorophenoxy2-iodophenyl 452 2,4-difluorophenoxy 4-pentylphenyl 3962,4-difluorophenoxy 2-(4-chlorophenylthio) 470 pyridin-3-yl2,4-difluorophenoxy 2,6-dimethylphenyl 354 2,4-difluorophenoxy2,5-dimethoxyphenyl 386 2,4-difluorophenoxy 2,5-dichloropyridin-3-yl 3962,4-difluorophenoxy 2-chloro-6-methoxypyridin- 392 4-yl2,4-difluorophenoxy 2,3-dichloropyridin-5-yl 396 2,4-difluorophenoxy1-naphthyl 390 2,4-difluorophenoxy 2,4-dimethoxyphenyl 3862,4-difluorophenoxy 3,5- 462 bis (trifluoromethyl)phenyl2,4-difluorophenoxy 2-(4- 454 chlorophenoxy)pyridin-3-yl2,4-difluorophenoxy pentafluorophenyl 416 4-thiomethylphenoxy3,4-dimethoxyphenyl 396 4-thiomethylphenoxy 2-(trifluoromethyl)phenyl404 4-thiomethylphenoxy 2,4-difluorophenyl 372 4-thiomethylphenoxy3-(trifluoromethyl)phenyl 404 4-thiomethylphenoxy 2-naphthyl 3864-thiomethylphenoxy 2-methoxyphenyl 366 4-thiomethylphenoxy3,4,5,-trimethylphenyl 426 4-thiomethylphenoxy 3,4-dichlorophenyl 4054-thiomethylphenoxy 3-bromophenyl 415 4-thiomethylphenoxy 3-pyridyl 3374-thiomethylphenoxy 2-ethoxynaphth-1-yl 430 4-thiomethylphenoxy2,3-dichlorophenyl 405 4-thiomethylphenoxy 6-chloropyrid-3-yl 3724-thiomethylphenoxy 4-(trifluoromethoxy)phenyl 420 4-thiomethylphenoxy2-fluoro-4- 422 (trifluoromethyl)phenyl 4-thiomethylphenoxy3-bromothienyl 421 4-thiomethylphenoxy 2-acetoxyphenyl 3944-thiomethylphenoxy 5-methylisoxazol-3-yl 341 4-thiomethylphenoxy2-(phenylthio)pyrid-3-yl 446 4-thiomethylphenoxy2-(trifluoromethoxy)phenyl 420 4-thiomethylphenoxy1-phenyl-5-propylpyrazin- 445 4-yl 4-thiomethylphenoxy 2-ethoxyphenyl380 4-thiomethylphenoxy 3-chlorothien-2-yl 377 4-thiomethylphenoxy1-(2-(2-methyl)propyl)-3- 396 methylpyrazol-5-yl 4-thiomethylphenoxy3,5-dichlorophenyl 405 4-thiomethylphenoxy 2-(propylthio)pyridin-3-yl412 4-thiomethylphenoxy 2-(ethylthio)pyridin-3-yl 3974-thiomethylphenoxy 3-bromopyridin-5-yl 416 4-thiomethylphenoxy4-methyl-1,2,3-thiadiazol- 358 5-yl 4-thiomethylphenoxy1-methyl-3-(2-(2- 396 methyl)propyl)pyrazol-5-yl 4-thiomethylphenoxy3-chlorobenzo[b]thiophen- 427 2-yl 4-thiomethylphenoxy 4-chlorophenyl371 4-thiomethylphenoxy 4-methyl-2-phenyl-1,2,3- 417 triazol-5-yl4-thiomethylphenoxy benzo[b]thiophen-2-yl 392 4-thiomethylphenoxy3,4-dimethylphenyl 364 4-thiomethylphenoxy 2-(phenoxy)pyridin-3-yl 4294-thiomethylphenoxy 2-(methylthiopyridin-3-yl 383 4-thiomethylphenoxy5-methyl-3-phenylisoxazol- 417 4-yl 4-thiomethylphenoxy4-chloro-1,3-dimethyl 440 pyrazolo[3,4-b]pyridin-3- yl4-thiomethylphenoxy 2-chloro-6-methylpyridin- 386 4-yl4-thiomethylphenoxy 3,5-dimethylisoxazol-4-yl 355 4-thiomethylphenoxy1-naphthyl 386 4-thiomethylphenoxy 2-fluorophenyl 3544-thiomethylphenoxy 4-propylphenyl 378 4-thiomethylphenoxy3-fluorophenyl 354 4-thiomethylphenoxy 2,6-difluorophenyl 3724-thiomethylphenoxy 2-chlorophenyl 371 4-thiomethylphenoxy3-(chloromethyl)phenyl 385 4-thiomethylphenoxy 4-(2-(2- 392methyl)propyl)phenyl 4-thiomethylphenoxy 3-chlorophenyl 3714-thiomethylphenoxy 3,5-dimethoxyphenyl 396 4-thiomethylphenoxy2,6-dichlorophenyl 405 4-thiomethylphenoxy 2,4-dichlorophenyl 4054-thiomethylphenoxy 4-fluorophenyl 354 4-thiomethylphenoxy 4-butylphenyl392 4-thiomethylphenoxy 2-methylphenyl 350 4-thiomethylphenoxy phenyl336 4-thiomethylphenoxy 4-ethylphenyl 364 4-thiomethylphenoxy2,3-difluorophenyl 372 4-thiomethylphenoxy 2,6-dimethoxyphenyl 3964-thiomethylphenoxy 3,4-difluorophenyl 372 4-thiomethylphenoxy2,5-difluorophenyl 372 4-thiomethylphenoxy 4-ethoxyphenyl 3804-thiomethylphenoxy 2,4,6-trichlorophenyl 440 4-thiomethylphenoxy3-methylphenyl 350 4-thiomethylphenoxy 2-fluoro-5- 422(trifluoromethyl)phenyl 4-thiomethylphenoxy 3-methoxyphenyl 3664-thiomethylphenoxy 2-bromophenyl 415 4-thiomethylphenoxy 4-bromophenyl415 4-thiomethylphenoxy 4-fluoro-3- 422 (trifluoromethyl)phenyl4-thiomethylphenoxy 3-(trifluoromethoxy)phenyl 420 4-thiomethylphenoxy9-fluorenon-4-yl 438 4-thiomethylphenoxy isoxazol-5-yl 3274-thiomethylphenoxy benzofuroxan-5-yl 394 4-thiomethylphenoxy2-chloropyrid-3-yl 372 4-thiomethylphenoxy 2-(4- 443methylphenoxy)pyridin-3-yl 4-thiomethylphenoxy pyridin-4-yl 3374-thiomethylphenoxy anthraquinon-2-yl 466 4-thiomethylphenoxy2-iodophenyl 462 4-thiomethylphenoxy 4-pentylphenyl 4074-thiomethylphenoxy 2-(4-chlorophenylthio) 480 pyridin-3-yl4-thiomethylphenoxy 2,6-dimethylphenyl 364 4-thiomethylphenoxy2,5-dimethoxyphenyl 396 4-thiomethylphenoxy 2,5-dichloropyridin-3-yl 4064-thiomethylphenoxy 2-chloro-6-methoxypyridin- 402 4-yl4-thiomethylphenoxy 2,3-dichloropyridin-5-yl 406 4-thiomethylphenoxy1-naphthyl 400 4-thiomethylphenoxy 2,4-dimethoxyphenyl 3964-thiomethylphenoxy 3,5- 372 bis(trifluoromethyl)phenyl4-thiomethylphenoxy 2-(4- 464 chlorophenoxy)pyridin-3-yl4-thiomethylphenoxy pentafluorophenyl 426 4-(2-(2- 3,4-dimethoxyphenyl406 methyl)propyl)phenoxy 4-(2-(2- 2-(trifluoromethyl)phenyl 414methyl)propyl)phenoxy 4-(2-(2- 2,4-difluorophenyl 382methyl)propyl)phenoxy 4-(2-(2- 3-(trifluoromethyl)phenyl 414methyl)propyl)phenoxy 4-(2-(2- 2-naphthyl 396 methyl)propyl)phenoxy4-(2-(2- 2-methoxyphenyl 376 methyl)propyl)phenoxy 4-(2-(2-3,4,5-trimethylphenyl 436 methyl)propyl)phenoxy 4-(2-(2-3,4-dichlorophenyl 415 methyl)propyl)phenoxy 4-(2-(2- 3-bromophenyl 425methyl)propyl)phenoxy 4-(2-(2- 3-pyridyl 347 methyl)propyl)phenoxy4-(2-(2- 2-ethoxynaphth-1-yl 441 methyl)propyl)phenoxy 4-(2-(2-2,3-dichlorophenyl 415 methyl)propyl)phenoxy 4-(2-(2- 6-chloropyrid-3-yl382 methyl)propyl)phenoxy 4-(2-(2- 4-(trifluoromethoxy)phenyl 430methyl)propyl)phenoxy 4-(2-(2- 2-fluoro-4- 432 methyl)propyl)phenoxy(trifluoromethyl)phenyl 4-(2-(2- 3-bromothienyl 431methyl)propyl)phenoxy 4-(2-(2- 2-acetoxyphenyl 404 methyl)propyl)phenoxy4-(2-(2- 5-methylisoxazol-3-yl 351 methyl)propyl)phenoxy 4-(2-(2-2-(phenylthio)pyrid-3-yl 456 methyl)propyl)phenoxy 4-(2-(2-2-(trifluoromethoxy)phenyl 430 methyl)propyl)phenoxy 4-(2-(2-1-phenyl-5-propylpyrazin- 455 methyl)propyl)phenoxy 4-yl 4-(2-(2-2-ethoxyphenyl 390 methyl)propyl)phenoxy 4-(2-(2- 3-chlorothien-2-yl 387methyl)propyl)phenoxy 4-(2-(2- 1-(2-(2-methyl)propyl)-3- 406methyl)propyl)phenoxy methylpyrazol-5-yl 4-(2-(2- 3,5-dichlorophenyl 415methyl)propyl)phenoxy 4-(2-(2- 2-(propylthio)pyridin-3-yl 422methyl)propyl)phenoxy 4-(2-(2- 2-(ethylthio)pyridin-3-yl 407methyl)propyl)phenoxy 4-(2-(2- 3-bromopyridin-5-yl 426methyl)propyl)phenoxy 4-(2-(2- 4-methyl-1,2,3-thiadiazol- 368methyl)propyl)phenoxy 5-yl 4-(2-(2- 1-methyl-3-(2-(2- 406methyl)propyl)phenoxy methyl)propyl)pyrazol-5-yl 4-(2-(2-3-chlorobenzo[b]thiophen- 437 methyl)propyl)phenoxy 2-yl 4-(2-(2-4-chlorophenyl 381 methyl)propyl)phenoxy 4-(2-(2-4-methyl-2-phenyl-1,2,3- 427 methyl)propyl)phenoxy triazol-5-yl 4-(2-(2-benzo[b]thiophen-2-yl 402 methyl)propyl)phenoxy 4-(2-(2-3,4-dimethylphenyl 374 methyl)propyl)phenoxy 4-(2-(2-2-(phenoxy)pyridin-3-yl 439 methyl)propyl)phenoxy 4-(2-(2-2-(methylthio)pyridin-3-yl 393 methyl)propyl)phenoxy 4-(2-(2-5-methyl-3-phenylisoxazol- 427 methyl)propyl)phenoxy 4-yl 4-(2-(2-4-chloro-1,3-dimethyl 450 methyl)propyl)phenoxypyrazolo[3,4-b]pyridin-3- yl 4-(2-(2- 2-chloro-6-methylpyridin- 396methyl)propyl)phenoxy 4-yl 4-(2-(2- 3,5-dimethylisoxazol-4-yl 365methyl)propyl)phenoxy 4-(2-(2- 1-naphthyl 396 methyl)propyl)phenoxy4-(2-(2- 2-fluorophenyl 364 methyl)propyl)phenoxy 4-(2-(2-4-propylphenyl 388 methyl)propyl)phenoxy 4-(2-(2- 3-fluorophenyl 364methyl)propyl)phenoxy 4-(2-(2- 2,6-difluorophenyl 382methyl)propyl)phenoxy 4-(2-(2- 2-chlorophenyl 381 methyl)propyl)phenoxy4-(2-(2- 3-(chloromethyl)phenyl 395 methyl)propyl)phenoxy 4-(2-(2-4-(2-(2- 402 methyl)propyl)phenoxy methyl)propyl)phenyl 4-(2-(2-3-chlorophenyl 381 methyl)propyl)phenoxy 4-(2-(2- 3,5-dimethoxyphenyl406 methyl)propyl)phenoxy 4-(2-(2- 2,6-dichlorophenyl 415methyl)propyl)phenoxy 4-(2-(2- 2,4-dichlorophenyl 415methyl)propyl)phenoxy 4-(2-(2- 4-fluorophenyl 364 methyl)propyl)phenoxy4-(2-(2- 4-butylphenyl 402 methyl)propyl)phenoxy 4-(2-(2- 2-methylphenyl360 methyl)propyl)phenoxy 4-(2-(2- phenyl 346 methyl)propyl)phenoxy4-(2-(2- 4-ethylphenyl 374 methyl)propyl)phenoxy 4-(2-(2-2,3-difluorophenyl 382 methyl)propyl)phenoxy 4-(2-(2-2,6-dimethoxyphenyl 406 methyl)propyl)phenoxy 4-(2-(2-3,4-difluorophenyl 382 methyl)propyl)phenoxy 4-(2-(2- 2,5-difluorophenyl382 methyl)propyl)phenoxy 4-(2-(2- 4-ethoxyphenyl 390methyl)propyl)phenoxy 4-(2-(2- 2,4,6-trichlorophenyl 450methyl)propyl)phenoxy 4-(2-(2- 3-methylphenyl 360 methyl)propyl)phenoxy4-(2-(2- 2-fluoro-5- 432 methyl)propyl)phenoxy (trifluoromethyl)phenyl4-(2-(2- 3-methoxyphenyl 376 methyl)propyl)phenoxy 4-(2-(2-2-bromophenyl 425 methyl)propyl)phenoxy 4-(2-(2- 4-bromophenyl 425methyl)propyl)phenoxy 4-(2-(2- 4-fluoro-3- 432 methyl)propyl)phenoxy(trifluoromethyl)phenyl 4-(2-(2- 3-(trifluoromethoxy)phenyl 430methyl)propyl)phenoxy 4-(2-(2- 9-fluorenon-4-yl 448methyl)propyl)phenoxy 4-(2-(2- isoxazol-5-yl 338 methyl)propyl)phenoxy4-(2-(2- benzofuroxan-5-yl 404 methyl)propyl)phenoxy 4-(2-(2-2-chloropyrid-3-yl 382 methyl)propyl)phenoxy 4-(2-(2- 2-(4- 454methyl)propyl)phenoxy methylphenoxy)pyridin-3-yl 4-(2-(2- pyridin-4-yl347 methyl)propyl)phenoxy 4-(2-(2- anthraquinon-2-yl 476methyl)propyl)phenoxy 4-(2-(2- 2-iodophenyl 472 methyl)propyl)phenoxy4-(2-(2- 4-pentylphenyl 417 methyl)propyl)phenoxy 4-(2-(2-2-(4-chlorophenylthio) 490 methyl)propyl)phenoxy pyridin-3-yl 4-(2-(2-2,6-dimethylphenyl 374 methyl)propyl)phenoxy 4-(2-(2-2,5-dimethoxyphenyl 406 methyl)propyl)phenoxy 4-(2-(2-2,5-dichloropyridin-3-yl 416 methyl)propyl)phenoxy 4-(2-(2-2-chloro-6-methoxypyridin- 412 methyl)propyl)phenoxy 4-yl 4-(2-(2-2,3-dichloropyridin-5-yl 416 methyl)propyl)phenoxy 4-(2-(2- 1-naphthyl410 methyl)propyl)phenoxy 4-(2-(2- 2,4-dimethoxyphenyl 406methyl)propyl)phenoxy 4-(2-(2- 3,5-bis(trifluoromethyl) 482methyl)propyl)phenoxy phenyl 4-(2-(2- 2-(4- 474 methyl)propyl)phenoxychlorophenoxy)pyridin-3-yl 4-(2-(2- pentafluorophenyl 436methyl)propyl)phenoxy 2,3-dimethylphenoxy 3,4-dimethoxyphenyl 3782,3-dimethylphenoxy 2-(trifluoromethyl)phenyl 386 213-dimethylphenoxy2,4-difluorophenyl 354 2,3-dimethylphenoxy 3-(trifluoromethyl)phenyl 3862,3-dimethylphenoxy 2-naphthyl 368 2,3-dimethylphenoxy 2-methoxyphenyl348 2,3-dimethylphenoxy 3,4,5-trimethylphenyl 408 2,3-dimethylphenoxy3,4-dichlorophenyl 387 2,3-dimethylphenoxy 3-bromophenyl 3972,3-dimethylphenoxy 3-pyridyl 319 2,3-dimethylphenoxy2-ethoxynaphth-1-yl 412 2,3-dimethylphenoxy 2,3-dichlorophenyl 3872,3-dimethylphenoxy 6-chloropyrid-3-yl 354 2,3-dimethylphenoxy4-(trifluoromethoxy)phenyl 402 2,3-dimethylphenoxy 2-fluoro-4- 404(trifluoromethyl)phenyl 2,3-dimethylphenoxy 3-bromothienyl 4032,3-dimethylphenoxy 2-acetoxyphenyl 376 2,3-dimethylphenoxy5-methylisoxazol-3-yl 323 2,3-dimethylphenoxy 2-(phenylthio)pyrid-3-yl427 2,3-dimethylphenoxy 2-(trifluoromethoxy)phenyl 4022,3-dimethylphenoxy 1-phenyl-5-propylpyrazin- 426 4-yl2,3-dimethylphenoxy 2-ethoxyphenyl 362 2,3-dimethylphenoxy3-chlorothien-2-yl 359 2,3-dimethylphenoxy 1-(2-(2-methyl)propyl)-3- 378methylpyrazol-5-yl 2,3-dimethylphenoxy 3,5-dichlorophenyl 3872,3-dimethylphenoxy 2-(propylthio)pyridin-3-yl 393 2,3-dimethylphenoxy2-(ethylthio)pyridin-3-yl 379 2,3-dimethylphenoxy 3-bromopyridin-5-yl398 2,3-dimethylphenoxy 4-methyl-1,2,3-thiadiazol- 340 5-yl2,3-dimethylphenoxy 1-methyl-3-(2-(2- 378 methyl)propyl)pyrazol-5-yl2,3-dimethylphenoxy 3-chlorobenzo[b]thiophen- 409 2-yl2,3-dimethylphenoxy 4-chlorophenyl 353 2,3-dimethylphenoxy4-methyl-2-phenyl-1,2,3- 399 triazol-5-yl 2,3-dimethylphenoxybenzo[b]thiophen-2-yl 374 2,3-dimethylphenoxy 3,4-dimethylphenyl 3462,3-dimethylphenoxy 2-(phenoxy)pyridin-3-yl 411 2,3-dimethylphenoxy2-(methylthio)pyridin-3-yl 365 2,3-dimethylphenoxy5-methyl-3-phenylisoxazol- 399 4-yl 2,3-dimethylphenoxy4-chloro-1,3-dimethyl 422 pyrazolo[3,4-b]pyridin-3- yl2,3-dimethylphenoxy 2-chloro-6-methylpyridin- 368 4-yl2,3-dimethylphenoxy 3,5-dimethylisoxazol-4-yl 337 2,3-dimethylphenoxy1-naphthyl 368 2,3-dimethylphenoxy 2-fluorophenyl 3362,3-dimethylphenoxy 4-propylphenyl 360 2,3-dimethylphenoxy3-fluorophenyl 336 2,3-dimethylphenoxy 2,6-difluorophenyl 3542,3-dimethylphenoxy 2-chlorophenyl 353 2,3-dimethylphenoxy3-(chloromethyl)phenyl 368 2,3-dimethylphenoxy 4-(2-(2-methyl)propyl)374 phenyl 2,3-dimethylphenoxy 3-chlorophenyl 353 2,3-dimethylphenoxy3,5-dimethoxyphenyl 378 2,3-dimethylphenoxy 2,6-dichlorophenyl 3872,3-dimethylphenoxy 2,4-dichlorophenyl 387 2,3-dimethylphenoxy4-fluorophenyl 336 2,3-dimethylphenoxy 4-butylphenyl 3742,3-dimethylphenoxy 2-methylphenyl 332 2,3-dimethylphenoxy phenyl 3182,3-dimethylphenoxy 4-ethylphenyl 346 2,3-dimethylphenoxy2,3-difluorophenyl 354 2,3-dimethylphenoxy 2,6-dimethoxyphenyl 3782,3-dimethylphenoxy 3,4-difluorophenyl 354 2,3-dimethylphenoxy2,5-difluorophenyl 354 2,3-dimethylphenoxy 4-ethoxyphenyl 3622,3-dimethylphenoxy 2,4,6-trichlorophenyl 422 2,3-dimethylphenoxy3-methylphenyl 332 2,3-dimethylphenoxy 2-fluoro-5- 404(trifluoromethyl)phenyl 2,3-dimethylphenoxy 3-methoxyphenyl 3482,3-dimethylphenoxy 2-bromophenyl 397 2,3-dimethylphenoxy 4-bromophenyl397 2,3-dimethylphenoxy 4-fluoro-3- 404 (trifluoromethyl)phenyl2,3-dimethylphenoxy 3-(trifluoromethoxy)phenyl 402 2,3-dimethylphenoxy9-fluorenon-4-yl 420 2,3-dimethylphenoxy isoxazol-5-yl 6092,3-dimethylphenoxy benzofuroxan-5-yl 376 2,3-dimethylphenoxy2-chloropyrid-3-yl 354 2,3-dimethylphenoxy 2-(4- 425methylphenoxy)pyridin-3-yl 2,3-dimethylphenoxy pyridin-4-yl 3192,3-dimethylphenoxy anthraquinon-2-yl 448 2,3-dimethylphenoxy2-iodophenyl 444 2,3-dimethylphenoxy 4-pentylphenyl 3882,3-dimethylphenoxy 2-(4-chlorophenylthio) 462 pyridin-3-yl2,3-dimethylphenoxy 2,6-dimethylphenyl 346 2,3-dimethylphenoxy2,5-dimethoxyphenyl 378 2,3-dimethylphenoxy 2,5-dichloropyridin-3-yl 3882,3-dimethylphenoxy 2-chloro-6-methoxypyridin- 384 4-yl2,3-dimethylphenoxy 2,3-dichloropyridin-5-yl 388 2,3-dimethylphenoxy1-naphthyl 382 2,3-dimethylphenoxy 2,4-dimethoxyphenyl 3782,3-dimethylphenoxy 3,5-bis(trifluoromethyl) 454 phenyl2,3-dimethylphenoxy 2-(4- 446 chlorophenoxyl pyridin-3-yl2,3-dimethylphenoxy pentafluorophenyl 408 3,5-(bis-2-3,4-dimethoxyphenyl 434 propyl)phenoxy 3,5-(bis-2-2-(trifluoromethyl)phenyl 442 propyl)phenoxy 3,5-(bis-2-2,4-difluorophenyl 410 propyl)phenoxy 3,5-(bis-2-3-(trifluoromethyl)phenyl 442 propyl)phenoxy 3,5-(bis-2- 2-naphthyl 425propyl)phenoxy 3,5-(bis-2- 2-methoxyphenyl 404 propyl)phenoxy3,5-(bis-2- 3,4,5-trimethylphenyl 465 propyl)phenoxy 3,5-(bis-2-3,4-dichlorophenyl 443 propyl)phenoxy 3,5-(bis-2- 3-bromophenyl 453propyl)phenoxy 3,5-(bis-2- 3-pyridyl 375 propyl)phenoxy 3,5-(bis-2-2-ethoxynaphth-1-yl 469 propyl)phenoxy 3,5-(bis-2- 2,3-dichlorophenyl443 propyl)phenoxy 3,5-(bis-2- 6-chloropyrid-3-yl 410 propyl)phenoxy3,5-(bis-2- 4-(trifluoromethoxy)phenyl 458 propyl)phenoxy 3,5-(bis-2-2-fluoro-4- 460 propyl)phenoxy (trifluoromethyl)phenyl 3,5-(bis-2-3-bromothienyl 459 propyl)phenoxy 3,5-(bis-2- 2-acetoxyphenyl 432propyl)phenoxy 3,5-(bis-2- 5-methylisoxazol-3-yl 379 propyl)phenoxy3,5-(bis-2- 2-(phenylthiopyrid-3-yl 484 propyl)phenoxy 3,5-(bis-2-2-(trifluoromethoxy)phenyl 458 propyl)phenoxy 3,5-(bis-2-1-phenyl-5-propylpyrazin- 483 propyl)phenoxy 4-yl 3,5-(bis-2-2-ethoxyphenyl 418 propyl)phenoxy 3,5-(bis-2- 3-chlorothiophen-2-yl 415propyl)phenoxy 3,5-(bis-2- 1-(2-(2-methyl)propyl)-3- 435 propyl)phenoxymethylpyrazol-5-yl 3,5-(bis-2- 3,5-dichlorophenyl 443 propyl)phenoxy3,5-(bis-2- 2-(propylthio)pyridin-3-yl 450 propyl)phenoxy 3,5-(bis-2-2-(ethylthio)pyridin-3-yl 436 propyl)phenoxy 3,5-(bis-2-3-bromopyridin-5-yl 454 propyl)phenoxy 3,5-(bis-2-4-methyl-1,2,3-thiadiazol- 396 propyl)phenoxy 5-yl 3,5-(bis-2-1-methyl-3-(2-(2- 435 propyl)phenoxy methyl)propyl)pyrazol-5-yl3,5-(bis-2- 3-chlorobenzo[b]thiophen- 465 propyl)phenoxy 2-yl3,5-(bis-2- 4-chlorophenyl 409 propyl)phenoxy 3,5-(bis-2-4-methyl-2-phenyl-1,2,3- 456 propyl)phenoxy triazol-5-yl 3,5-(bis-2-benzo[b]thiophen-2-yl 431 propyl)phenoxy 3,5-(bis-2- 3,4-dimethylphenyl402 propyl)phenoxy 3,5-(bis-2- 2-(phenoxy)pyridin-3-yl 468propyl)phenoxy 3,5-(bis-2- 2-(methylthio)pyridin-3-yl 422 propyl)phenoxy315-(bis-2- 5-methyl-3-phenylisoxazol- 456 propyl)phenoxy 4-yl3,5-(bis-2- 4-chloro-1,3-dimethyl 478 propyl)phenoxypyrazolo[3,4-b]pyridin-3- yl 3,5-(bis-2- 2-chloro-6-methylpyridin- 424propyl)phenoxy 4-yl 3,5-(bis-2- 3,5-dimethylisoxazol-4-yl 393propyl)phenoxy 3,5-(bis-2- 1-naphthyl 425 propyl)phenoxy 3,5-(bis-2-2-fluorophenyl 392 propyl)phenoxy 3,5-(bis-2- 4-propylphenyl 417propyl)phenoxy 3,5-(bis-2- 3-fluorophenyl 392 propyl)phenoxy 3,5-(bis-2-2,6-difluorophenyl 410 propyl)phenoxy 3,5-(bis-2- 2-chlorophenyl 409propyl)phenoxy 315-(bis-2- 3-(chloromethyl)phenyl 423 propyl)phenoxy3,5-(bis-2- 4-(2-(2-methyl)propyl) 431 propyl)phenoxy phenyl 3,5-(bis-2-3-chlorophenyl 409 propyl)phenoxy 3,5-(bis-2- 3,5-dimethoxyphenyl 434propyl)phenoxy 3,5-(bis-2- 2,6-dichlorophenyl 443 propyl)phenoxy3,5-(bis-2- 2,4-dichlorophenyl 443 propyl)phenoxy 3,5-(bis-2-4-fluorophenyl 392 propyl)phenoxy 3,5-(bis-2- 4-butylphenyl 431propyl)phenoxy 3,5-(bis-2- 2-methylphenyl 388 propyl)phenoxy 3,5-(bis-2-phenyl 374 propyl)phenoxy 3,5-(bis-2- 4-ethylphenyl 402 propyl)phenoxy3,5-(bis-2- 2,3-difluorophenyl 410 propyl)phenoxy 3,5-(bis-2-2,6-dimethoxyphenyl 434 propyl)phenoxy 3,5-(bis-2- 3,4-difluorophenyl410 propyl)phenoxy 3,5-(bis-2- 2,5-difluorophenyl 410 propyl)phenoxy3,5-(bis-2- 4-ethoxyphenyl 418 propyl)phenoxy 3,5-(bis-2-2,4,6-trichlorophenyl 478 propyl)phenoxy 3,5-(bis-2- 3-methylphenyl 388propyl)phenoxy 3,5-(bis-2- 2-fluoro-5- 460 propyl)phenoxy(trifluoromethyl)phenyl 3,5-(bis-2- 3-methoxyphenyl 404 propyl)phenoxy3,5-(bis-2- 2-bromophenyl 453 propyl)phenoxy 3,5-(bis-2- 4-bromophenyl453 propyl)phenoxy 3,5-(bis-2- 4-fluoro-3- 460 propyl)phenoxy(trifluoromethyl)phenyl 3,5-(bis-2- 3-(trifluoromethoxy)phenyl 458propyl)phenoxy 3,5-(bis-2- 9-fluorenon-4-yl 477 propyl)phenoxy3,5-(bis-2- isoxazol-5-yl 365 propyl)phenoxy 3,5-(bis-2-benzofuroxan-5-yl 432 propyl)phenoxy 3,5-(bis-2- 2-chloropyrid-3-yl 410propyl)phenoxy 3,5-(bis-2- 2-(4- 482 propyl)phenoxymethylphenoxy)pyridin-3-yl 3,5-(bis-2- pyridin-4-yl 375 propyl)phenoxy3,5-(bis-2- anthraquinon-2-yl 505 propyl)phenoxy 3,5-(bis-2-2-iodophenyl 500 propyl)phenoxy 3,5-(bis-2- 4-pentylphenyl 445propyl)phenoxy 3,5-(bis-2- 2-(4-chlorophenylthio) 518 propyl)phenoxypyridin-3-yl 3,5-(bis-2- 2,6-dimethylphenyl 402 propyl)phenoxy3,5-(bis-2- 2,5-dimethoxyphenyl 434 propyl)phenoxy 3,5-(bis-2-2,5-dichloropyridin-3-yl 444 propyl)phenoxy 3,5-(bis-2-2-chloro-6-methoxypyridin- 440 propyl)phenoxy 4-yl 3,5-(bis-2-2,3-dichloropyridin-5-yl 444 propyl)phenoxy 3,5-(bis-2- 1-naphthyl 439propyl)phenoxy 3,5-(bis-2- 2,4-dimethoxyphenyl 434 propyl)phenoxy3,5-(bis-2- 3,5-bis(trifluoromethyl) 510 propyl)phenoxy phenyl3,5-(bis-2- 2-(4- 502 propyl)phenoxy chlorophenoxy)pyridin-3-yl3,5-(bis-2- pentafluorophenyl 464 propyl)phenoxy 3-trifluoromethyl3,4-dimethoxyphenyl 418 phenoxy 3-trifluoromethyl2-(trifluoromethyl)phenyl 426 phenoxy 3-trifluoromethyl2,4-difluorophenyl 394 phenoxy 3-trifluoromethyl3-(trifluoromethyl)phenyl 426 phenoxy 3-trifluoromethyl 2-naphthyl 408phenoxy 3-trifluoromethyl 2-methoxyphenyl 388 phenoxy 3-trifluoromethyl3,4,5-trimethylphenyl 448 phenoxy 3-trifluoromethyl 3,4-dichlorophenyl427 phenoxy 3-trifluoromethyl 3-bromophenyl 437 phenoxy3-trifluoromethyl 3-pyridyl 359 phenoxy 3-trifluoromethyl2-ethoxynaphth-1-yl 452 phenoxy 3-trifluoromethyl 2,3-dichlorophenyl 427phenoxy 3-trifluoromethyl 6-chloropyrid-3-yl 394 phenoxy3-trifluoromethyl 4-(trifluoromethoxy)phenyl 442 phenoxy3-trifluoromethyl 2-fluoro-4- 444 phenoxy (trifluoromethyl)phenyl3-trifluoromethyl 3-bromothienyl 443 phenoxy 3-trifluoromethyl2-acetoxyphenyl 416 phenoxy 3-trifluoromethyl 5-methylisoxazol-3-yl 363phenoxy 3-trifluoromethyl 2-(phenylthio)pyrid-3-yl 467 phenoxy3-trifluoromethyl 2-(trifluoromethoxy)phenyl 442 phenoxy3-trifluoromethyl 1-phenyl-5-propylpyrazin- 466 phenoxy 4-yl3-trifluoromethyl 2-ethoxyphenyl 402 phenoxy 3-trifluoromethyl3-chlorothien-2-yl 399 phenoxy 3-trifluoromethyl1-(2-(2-methyl)propyl)-3- 418 phenoxy methylpyrazol-5-yl3-trifluoromethyl 3,5-dichlorophenyl 427 phenoxy 3-trifluoromethyl2-(propylthio)pyridin-3-yl 433 phenoxy 3-trifluoromethyl2-(ethylthio)pyridin-3-yl 419 phenoxy 3-trifluoromethyl3-bromopyridin-5-yl 438 phenoxy 3-trifluoromethyl4-methyl-1,2,3-thiadiazol- 380 phenoxy 5-yl 3-trifluoromethyl1-methyl-3-(2-(2- 418 phenoxy methyl)propyl)pyrazol-5-yl3-trifluoromethyl 3-chlorobenzo[b]thiophen- 449 phenoxy 2-yl3-trifluoromethyl 4-chlorophenyl 393 phenoxy 3-trifluoromethyl4-methyl-2-phenyl-1,2,3- 439 phenoxy triazol-5-yl 3-trifluoromethylbenzo[b]thiophen-2-yl 414 phenoxy 3-trifluoromethyl 3,4-dimethylphenyl386 phenoxy 3-trifluoromethyl 2-(phenoxy)pyridin-3-yl 451 phenoxy3-trifluoromethyl 2-(methylthio)pyridin-3-yl 405 phenoxy3-trifluoromethyl 5-methyl-3-phenylisoxazol- 439 phenoxy 4-yl3-trifluoromethyl 4-chloro-1,3-dimethyl 462 phenoxypyrazolo[3,4-b]pyridin-3- yl 3-trifluoromethyl 2-chloro-6-methylpyridin-408 phenoxy 4-yl 3-trifluoromethyl 3,5-dimethylisoxazol-4-yl 377 phenoxy3-trifluoromethyl 1-naphthyl 408 phenoxy 3-trifluoromethyl2-fluorophenyl 476 phenoxy 3-trifluoromethyl 4-propylphenyl 400 phenoxy3-trifluoromethyl 3-fluorophenyl 376 phenoxy 3-trifluoromethyl2,6-difluorophenyl 394 phenoxy 3-trifluoromethyl 2-chlorophenyl 393phenoxy 3-trifluoromethyl 3-(chloromethyl)phenyl 407 phenoxy3-trifluoromethyl 4-(2-(2-methyl)propyl) 414 phenoxy phenyl3-trifluoromethyl 3-chlorophenyl 393 phenoxy 3-trifluoromethyl3,5-dimethoxyphenyl 418 phenoxy 3-trifluoromethyl 2,6-dichlorophenyl 427phenoxy 3-trifluoromethyl 2,4-dichlorophenyl 427 phenoxy3-trifluoromethyl 4-fluorophenyl 376 phenoxy 3-trifluoromethyl4-butylphenyl 414 phenoxy 3-trifluoromethyl 2-methylphenyl 372 phenoxy3-trifluoromethyl phenyl 358 phenoxy 3-trifluoromethyl 4-ethylphenyl 386phenoxy 3-trifluoromethyl 2,3-difluorophenyl 394 phenoxy3-trifluoromethyl 2,6-dimethoxyphenyl 418 phenoxy 3-trifluoromethyl3,4-difluorophenyl 394 phenoxy 3-trifluoromethyl 2,5-difluorophenyl 394phenoxy 3-trifluoromethyl 4-ethoxyphenyl 402 phenoxy 3-trifluoromethyl2,4,6-trichlorophenyl 462 phenoxy 3-trifluoromethyl 3-methylphenyl 372phenoxy 3-trifluoromethyl 2-fluoro-5- 444 phenoxy(trifluoromethyl)phenyl 3-trifluoromethyl 3-methoxyphenyl 388 phenoxy3-trifluoromethyl 2-bromophenyl 437 phenoxy 3-trifluoromethyl4-bromophenyl 437 phenoxy 3-trifluoromethyl 4-fluoro-3- 444 phenoxy(trifluoromethyl)phenyl 3-trifluoromethyl 3-(trifluoromethoxy)phenyl 442phenoxy 3-trifluoromethyl 9-fluorenon-4-yl 460 phenoxy 3-trifluoromethylisoxazol-5-yl 349 phenoxy 3-trifluoromethyl benzofuroxan-5-yl 416phenoxy 3-trifluoromethyl 2-chloropyrid-3-yl 394 phenoxy3-trifluoromethyl 2-(4- 465 phenoxy methylphenoxy)pyridin-3-yl3-trifluoromethyl pyridin-4-yl 359 phenoxy 3-trifluoromethylanthraquinon-2-yl 488 phenoxy 3-trifluoromethyl 2-iodophenyl 484 phenoxy3-trifluoromethyl 4-pentylphenyl 428 phenoxy 3-trifluoromethyl2-(4-chlorophenylthio) 502 phenoxy pyridin-3-yl 3-trifluoromethyl2,6-dimethylphenyl 386 phenoxy 3-trifluoromethyl 2,5-dimethoxyphenyl 418phenoxy 3-trifluoromethyl 2,5-dichloropyridin-3-yl 428 phenoxy3-trifluoromethyl 2-chloro-6-methoxypyridin- 424 phenoxy 4-yl3-trifluoromethyl 2,3-dichloropyridin-5-yl 428 phenoxy 3-trifluoromethyl1-naphthyl 422 phenoxy 3-trifluoromethyl 2,4-dimethoxyphenyl 418 phenoxy3-trifluoromethyl 3,5- 494 phenoxy bis (trifluoromethyl)phenyl3-trifluoromethyl 2-(4- 486 phenoxy chlorophenoxy)pyridin-3-yl3-trifluoromethyl pentafluorophenyl 448 phenoxy 2,6-dichlorophenoxy3,4-dimethoxyphenyl 419 2,6-dichlorophenoxy 2-(trifluoromethyl)phenyl427 2,6-dichlorophenoxy 2,4-difluorophenyl 395 2,6-dichlorophenoxy3-(trifluoromethyl)phenyl 427 2,6-dichlorophenoxy 2-naphthyl 4092,6-dichlorophenoxy 2-methoxyphenyl 389 2,6-dichlorophenoxy3,4,5-trimethylphenyl 449 2,6-dichlorophenoxy 3,4-dichlorophenyl 4282,6-dichlorophenoxy 3-bromophenyl 438 2,6-dichlorophenoxy 3-pyridyl 3612,6-dichlorophenoxy 2-ethoxynaphth-1-yl 453 2,6-dichlorophenoxy2,3-dichlorophenyl 428 2,6-dichlorophenoxy 6-chloropyrid-3-yl 3952,6-dichlorophenoxy 4-(trifluoromethoxy)phenyl 443 2,6-dichlorophenoxy2-fluoro-4- 445 (trifluoromethyl)phenyl 2,6-dichlorophenoxy3-bromothienyl 444 2,6-dichlorophenoxy 2-acetoxyphenyl 4172,6-dichlorophenoxy 5-methylisoxazol-3-yl 364 2,6-dichlorophenoxy2-(phenylthio)pyrid-3-yl 468 2,6-dichlorophenoxy2-(trifluoromethoxy)phenyl 443 2,6-dichlorophenoxy1-phenyl-5-propylpyrazin- 467 4-yl 2,6-dichlorophenoxy 2-ethoxypheny)403 2,6-dichlorophenoxy 3-chlorothien-2-yl 400 2,6-dichlorophenoxy1-(2-(2-methyl)propyl)-3- 419 methylpyrazol-5-yl 2,6-dichlorophenoxy3,5-dichlorophenyl 428 2,6-dichlorophenoxy 2-(propylthio)pyridin-3-yl434 2,6-dichlorophenoxy 2-(ethylthio)pyridin-3-yl 4202,6-dichlorophenoxy 3-bromopyridin-5-yl 439 2,6-dichlorophenoxy4-methyl-1,2,3-thiadiazol- 381 5-yl 2,6-dichlorophenoxy1-methyl-3-(2-(2- 419 methyl)propyl)pyrazol-5-yl 2,6-dichlorophenoxy3-chlorobenzo[b]thiophen- 450 2-yl 2,6-dichlorophenoxy 4-chlorophenyl394 2,6-dichlorophenoxy 4-methyl-2-phenyl-1,2,3- 440 triazol-5-yl2,6-dichlorophenoxy benzo[b]thiophen-2-yl 415 2,6-dichlorophenoxy3,4-dimethylphenyl 387 2,6-dichlorophenoxy 2-(phenoxy)pyridin-3-yl 4522,6-dichlorophenoxy 2-(methylthio)pyridin-3-yl 406 2,6-dichlorophenoxy5-methyl-3-phenylisoxazol- 440 4-yl 2,6-dichlorophenoxy4-chloro-1,3-dimethyl 463 pyrazolo[3,4-b]pyridin-3- yl2,6-dichlorophenoxy 2-chloro-6-methylpyridin- 409 4-yl2,6-dichlorophenoxy 3,5-dimethylisoxazol-4-yl 378 2,6-dichlorophenoxy1-naphthyl 409 2,6-dichlorophenoxy 2-fluorophenyl 3772,6-dichlorophenoxy 4-propylphenyl 401 2,6-dichlorophenoxy3-fluorophenyl 377 2,6-dichlorophenoxy 2,6-difluorophenyl 3952,6-dichlorophenoxy 2-chlorophenyl 394 2,6-dichlorophenoxy3-(chloromethyl)phenyl 408 2,6-dichlorophenoxy 4-(2-(2-methyl)propyl)415 phenyl 2,6-dichlorophenoxy 3-chlorophenyl 694 2,6-dichlorophenoxy3,5-dimethoxyphenyl 419 2,6-dichlorophenoxy 2,6-dichlorophenyl 4282,6-dichlorophenoxy 2,4-dichlorophenyl 428 2,6-dichlorophenoxy4-fluorophenyl 377 2,6-dichlorophenoxy 4-butylphenyl 4152,6-dichlorophenoxy 2-methylphenyl 373 2,6-dichlorophenoxy phenyl 3592,6-dichlorophenoxy 4-ethylphenyl 387 2,6-dichlorophenoxy2,3-difluorophenyl 395 2,6-dichlorophenoxy 2,6-dimethoxyphenyl 4192,6-dichlorophenoxy 3,4-difluorophenyl 395 2,6-dichlorophenoxy2,5-difluorophenyl 395 2,6-dichlorophenoxy 4-ethoxyphenyl 4032,6-dichlorophenoxy 2,4,6-trichlorophenyl 463 2,6-dichlorophenoxy3-methylphenyl 373 2,6-dichlorophenoxy 2-fluoro-5- 445(trifluoromethyl)phenyl 2,6-dichlorophenoxy 3-methoxyphenyl 3892,6-dichlorophenoxy 2-bromophenyl 438 2,6-dichlorophenoxy 4-bromophenyl438 2,6-dichlorophenoxy 4-fluoro-3- 445 (trifluoromethyl)phenyl2,6-dichlorophenoxy 3-(trifluoromethoxy)phenyl 443 2,6-dichlorophenoxy9-fluorenon-4-yl 461 2,6-dichlorophenoxy isoxazol-5-yl 3502,6-dichlorophenoxy benzofuroxan-5-yl 417 2,6-dichlorophenoxy2-chloropyrid-3-yl 395 2,6-dichlorophenoxy 2-(4- 466methylphenoxy)pyridin-3-yl 2,6-dichlorophenoxy pyridin-4-yl 3602,6-dichlorophenoxy anthraquinon-2-yl 489 2,6-dichlorophenoxy2-iodophenyl 485 2,6-dichlorophenoxy 4-pentylphenyl 4292,6-dichlorophenoxy 2-(4-chlorophenylthio) 503 pyridin-3-yl2,6-dichlorophenoxy 2,6-dimethylphenyl 387 2,6-dichlorophenoxy2,5-dimethoxyphenyl 419 2,6-dichlorophenoxy 2,5-dichloropyridin-3-yl 4292,6-dichlorophenoxy 2-chloro-6-methoxypyridin- 425 4-yl2,6-dichlorophenoxy 2,3-dichloropyridin-5-yl 429 2,6-dichlorophenoxy1-naphthyl 413 2,6-dichlorophenoxy 2,4-dimethoxyphenyl 4192,6-dichlorophenoxy 3,5- 495 bis(trifluoromethyl)phenyl2,6-dichlorophenoxy 2-(4- 487 chlorophenoxy)pyridin-3-yl2,6-dichlorophenoxy pentafluorophenyl 449 2,4-dichlorophenoxy3,4-dimethoxyphenyl 419 2,4-dichlorophenoxy 2-(trifluoromethyl)phenyl427 2,4-dichlorophenoxy 2,4-difluorophenyl 395 2,4-dichlorophenoxy3-(trifluoromethyl)phenyl 427 2,4-dichlorophenoxy 2-naphthyl 4092,4-dichlorophenoxy 2-methoxyphenyl 389 2,4-dichlorophenoxy3,4,5-trimethylphenyl 449 2,4-dichlorophenoxy 3,4-dichlorophenyl 4282,4-dichlorophenoxy 3-bromophenyl 438 2,4-dichlorophenoxy 3-pyridyl 3612,4-dichlorophenoxy 2-ethoxynaphth-1-yl 453 2,4-dichlorophenoxy2,3-dichlorophenyl 428 2,4-dichlorophenoxy 6-chloropyrid-3-yl 3952,4-dichlorophenoxy 4-(trifluoromethoxy)phenyl 443 2,4-dichlorophenoxy2-fluoro-4- 445 (trifluoromethyl)phenyl 2,4-dichlorophenoxy3-bromothienyl 444 2,4-dichlorophenoxy 2-acetoxyphenyl 4172,4-dichlorophenoxy 5-methylisoxazol-3-yl 364 2,4-dichlorophenoxy2-(phenylthio)pyrid-3-yl 468 2,4-dichlorophenoxy2-(trifluoromethoxy)phenyl 443 2,4-dichlorophenoxy1-phenyl-5-propylpyrazin- 467 4-yl 2,4-dichlorophenoxy 2-ethoxyphenyl403 2,4-dichlorophenoxy 3-chlorothien-2-yl 400 2,4-dichlorophenoxy1-(2-(2-methyl)propyl)-3- 419 methylpyrazol-5-yl 2,4-dichlorophenoxy3,5-dichlorophenyl 428 2,4-dichlorophenoxy 2-(propylthio)pyridin-3-yl434 2,4-dichlorophenoxy 2-(ethylthio)pyridin-3-yl 4202,4-dichlorophenoxy 3-bromopyridin-5-yl 439 2,4-dichlorophenoxy4-methyl-1,2,3-thiadiazol- 381 5-yl 2,4-dichlorophenoxy1-methyl-3-(2-(2- 419 methyl)propyl)pyrazol-5-yl 2,4-dichlorophenoxy3-chlorobenzo[b]thiophen- 450 2-yl 2,4-dichlorophenoxy 4-chlorophenyl394 2,4-dichlorophenoxy 4-methyl-2-phenyl-1,2,3- 440 triazol-5-yl2,4-dichlorophenoxy benzo[b]thiophen-2-yl 415 2,4-dichlorophenoxy3,4-dimethylphenyl 387 2,4-dichlorophenoxy 2-(phenoxy)pyridin-3-yl 4522,4-dichlorophenoxy 2-(methylthio)pyridin-3-yl 406 2,4-dichlorophenoxy5-methyl-3-phenylisoxazol- 440 4-yl 2,4-dichlorophenoxy4-chloro-1,3-dimethyl 463 pyrazolo[3,4-b]pyridin-3- yl2,4-dichlorophenoxy 2-chloro-6-methylpyridin- 409 4-yl2,4-dichlorophenoxy 3,5-dimethylisoxazol-4-yl 378 2,4-dichlorophenoxy1-naphthyl 409 2,4-dichlorophenoxy 2-fluorophenyl 3772,4-dichlorophenoxy 4-propylphenyl 401 2,4-dichlorophenoxy3-fluorophenyl 377 2,4-dichlorophenoxy 2,6-difluorophenyl 3952,4-dichlorophenoxy 2-chlorophenyl 394 2,4-dichlorophenoxy3-(chloromethyl)phenyl 408 2,4-dichlorophenoxy 4-(2-(2- 415methyl)propyl)phenyl 2,4-dichlorophenoxy 3-chlorophenyl 6942,4-dichlorophenoxy 3,5-dimethoxyphenyl 419 2,4-dichlorophenoxy2,6-dichlorophenyl 428 2,4-dichlorophenoxy 2,4-dichlorophenyl 4282,4-dichlorophenoxy 4-fluorophenyl 377 2,4-dichlorophenoxy 4-butylphenyl415 2,4-dichlorophenoxy 2-methylphenyl 373 2,4-dichlorophenoxy phenyl359 2,4-dichlorophenoxy 4-ethylphenyl 387 2,4-dichlorophenoxy2,3-difluorophenyl 395 2,4-dichlorophenoxy 2,6-dimethoxyphenyl 4192,4-dichlorophenoxy 3,4-difluorophenyl 395 2,4-dichlorophenoxy2,5-difluorophenyl 395 2,4-dichlorophenoxy 4-ethoxyphenyl 4032,4-dichlorophenoxy 2,4,6-trichlorophenyl 463 2,4-dichlorophenoxy3-methylphenyl 373 2,4-dichlorophenoxy 2-fluoro-5- 445(trifluoromethyl)phenyl 2,4-dichlorophenoxy 3-methoxyphenyl 3892,4-dichlorophenoxy 2-bromophenyl 438 2,4-dichlorophenoxy 4-bromophenyl438 2,4-dichlorophenoxy 4-fluoro-3- 445 (trifluoromethyl)phenyl2,4-dichlorophenoxy 3-(trifluoromethoxy)phenyl 443 2,4-dichlorophenoxy9-fluorenon-4-yl 461 2,4-dichlorophenoxy isoxazol-5-yl 3502,4-dichlorophenoxy benzofuroxan-5-yl 417 2,4-dichlorophenoxy2-chloropyrid-3-yl 395 2,4-dichlorophenoxy 2-(4- 466methylphenoxy)pyridin-3-yl 2,4-dichlorophenoxy pyridin-4-yl 3602,4-dichlorophenoxy anthraquinon-2-yl 489 2,4-dichlorophenoxy2-iodophenyl 485 2,4-dichlorophenoxy 4-pentylphenyl 4292,4-dichlorophenoxy 2-(4-chlorophenylthio) 503 pyridin-3-yl2,4-dichlorophenoxy 2,6-dimethylphenyl 387 2,4-dichlorophenoxy2,5-dimethoxyphenyl 419 2,4-dichlorophenoxy 2,5-dichloropyridin-3-yl 4292,4-dichlorophenoxy 2-chloro-6-methoxypyridin- 425 4-yl2,4-dichlorophenoxy 2,3-dichloropyridin-5-yl 429 2,4-dichlorophenoxy1-naphthyl 413 2,4-dichlorophenoxy 2,4-dimethoxyphenyl 4192,4-dichlorophenoxy 3,5- 495 bis(trifluoromethyl)phenyl2,4-dichlorophenoxy 2-(4- 487 chlorophenoxy)pyridin-3-yl2,4-dichlorophenoxy pentafluorophenyl 449 4-chloro-3-3,4-dimethoxyphenyl 319 methylphenoxy 4-chloro-3-2-(trifluoromethyl)phenyl 407 methylphenoxy 4-chloro-3-2,4-difluorophenyl 375 methylphenoxy 4-chloro-3-3-(trifluoromethyl)phenyl 407 methylphenoxy 4-chloro-3- 2-naphthyl 389methylphenoxy 4-chloro-3- 2-methoxyphenyl 369 methylphenoxy 4-chloro-3-3,4,5-trimethylphenyl 429 methylphenoxy 4-chloro-3- 3,4-dichlorophenyl408 methylphenoxy 4-chloro-3- 3-bromophenyl 418 methylphenoxy4-chloro-3- 3-pyridyl 340 methylphenoxy 4-chloro-3- 2-ethoxynaphth-1-yl433 methylphenoxy 4-chloro-3- 2,3-dichlorophenyl 408 methylphenoxy4-chloro-3- 6-chloropyrid-3-yl 374 methylphenoxy 4-chloro-3-4-(trifluoromethoxy)phenyl 423 methylphenoxy 4-chloro-3- 2-fluoro-4- 425methylphenoxy (trifluoromethyl)phenyl 4-chloro-3- 3-bromothienyl 424methylphenoxy 4-chloro-3- 2-acetoxyphenyl 397 methylphenoxy 4-chloro-3-5-methylisoxazol-3-yl 344 methylphenoxy 4-chloro-3-2-(phenylthio)pyrid-3-yl 448 methylphenoxy 4-chloro-3-2-(trifluoromethoxy)phenyl 423 methylphenoxy 4-chloro-3-1-phenyl-5-propylpyrazin- 447 methylphenoxy 4-yl 4-chloro-3-2-ethoxyphenyl 383 methylphenoxy 4-chloro-3- 3-chlorothien-2-yl 379methylphenoxy 4-chloro-3- 1-(2-(2-methyl)propyl)-3- 399 methylphenoxymethylpyrazol-5-yl 4-chloro-3- 3,5-dichlorophenyl 408 methylphenoxy4-chloro-3- 2-(propylthio)pyridin-3-yl 414 methylphenoxy 4-chloro-3-2-(ethylthio)pyridin-3-yl 400 methylphenoxy 4-chloro-3-3-bromopyridin-5-yl 419 methylphenoxy 4-chloro-3-4-methyl-1,2,3-thiadiazol- 361 methylphenoxy 5-yl 4-chloro-3-1-methyl-3-(2-(2- 399 methylphenoxy methyl)propyl)pyrazol-5-yl4-chloro-3- 3-chlorobenzo[b]thiophen- 429 methylphenoxy 2-yl 4-chloro-3-4-chlorophenyl 373 methylphenoxy 4-chloro-3- 4-methyl-2-phenyl-1,2,3-420 methylphenoxy triazol-5-yl 4-chloro-3- benzo[b]thiophen-2-yl 395methylphenoxy 4-chloro-3- 3,4-dimethylphenyl 367 methylphenoxy4-chloro-3- 2-(phenoxy)pyridin-3-yl 432 methylphenoxy 4-chloro-3-2-(methylthio)pyridin-3-yl 386 methylphenoxy 4-chloro-3-5-methyl-3-phenylisoxazol- 420 methylphenoxy 4-yl 4-chloro-3-4-chloro-1,3-dimethyl 442 methylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-3- 2-chloro-6-methylpyridin- 388 methylphenoxy 4-yl 4-chloro-3-3,5-dimethylisoxazol-4-yl 358 methylphenoxy 4-chloro-3- 1-naphthyl 389methylphenoxy 4-chloro-3- 2-fluorophenyl 357 methylphenoxy 4-chloro-3-4-propylphenyl 381 methylphenoxy 4-chloro-3- 4-(trifluoromethyl)phenyl407 methylphenoxy 4-chloro-3- 3-fluorophenyl 357 methylphenoxy4-chloro-3- 2,6-difluorophenyl 375 methylphenoxy 4-chloro-3-2-chlorophenyl 373 methylphenoxy 4-chloro-3- 3-(chloromethyl)phenyl 387methylphenoxy 4-chloro-3- 4-(2-(2- 395 methylphenoxymethyl)propyl)phenyl 4-chloro-3- 3-chlorophenyl 373 methylphenoxy4-chloro-3- 3,5-dimethoxyphenyl 399 methylphenoxy 4-chloro-3-2,6-dichlorophenyl 408 methylphenoxy 4-chloro-3- 2,4-dichlorophenyl 408methylphenoxy 4-chloro-3- 4-fluorophenyl 357 methylphenoxy 4-chloro-3-4-butylphenyl 395 methylphenoxy 4-chloro-3- 2-methylphenyl 353methylphenoxy 4-chloro-3- phenyl 339 methylphenoxy 4-chloro-3-4-ethylphenyl 367 methylphenoxy 4-chloro-3- 2,3-difluorophenyl 375methylphenoxy 4-chloro-3- 2,6-dimethoxyphenyl 399 methylphenoxy4-chloro-3- 3,4-difluorophenyl 375 methylphenoxy 4-chloro-3-2,5-difluorophenyl 375 methylphenoxy 4-chloro-3- 4-ethoxyphenyl 383methylphenoxy 4-chloro-3- 2,4,6-trichlorophenyl 442 methylphenoxy4-chloro-3- 3-methylphenyl 353 methylphenoxy 4-chloro-3- 2-fluoro-5- 425methylphenoxy (trifluoromethyl)phenyl 4-chloro-3- 3-methoxyphenyl 369methylphenoxy 4-chloro-3- 2-bromophenyl 418 methylphenoxy 4-chloro-3-4-bromophenyl 418 methylphenoxy 4-chloro-3- 4-fluoro-3- 425methylphenoxy (trifluoromethyl-)phenyl 4-chloro-3-3-(trifluoromethoxy)phenyl 423 methylphenoxy 4-chloro-3-9-fluorenon-4-yl 441 methylphenoxy 4-chloro-3- isoxazol-5-yl 330methylphenoxy 4-chloro-3- benzofuroxan-5-yl 397 methylphenoxy4-chloro-3- 2-chloropyrid-3-yl- 374 methylphenoxy 4-chloro-3- 2-(4- 446methylphenoxy methylphenoxy)pyridin-3-yl 4-chloro-3- pyridin-4-yl 340methylphenoxy 4-chloro-3- anthraquinon-2-yl 469 methylphenoxy4-chloro-3- 2-iodophenyl 465 methylphenoxy 4-chloro-3- 4-pentylphenyl409 methylphenoxy 4-chloro-3- 2-(4-chlorophenylthio) 482 methylphenoxypyridin-3-yl 4-chloro-3- 2,6-dimethylphenyl 367 methylphenoxy4-chloro-3- 2,5-dimethoxyphenyl 399 methylphenoxy 4-chloro-3-2,5-dichloropyridin-3-yl 409 methylphenoxy 4-chloro-3-2-chloro-6-methoxypyridin- 404 methylphenoxy 4-yl 4-chloro-3-2,3-dichloropyridin-5-yl 409 methylphenoxy 4-chloro-3- 1-naphthyl 403methylphenoxy 4-chloro-3- 2,4-dimethoxyphenyl 399 methylphenoxy4-chloro-3- 3,5- 475 methylphenoxy bis (trifluoromethyl)phenyl4-chloro-3- 2-(4- 466 methylphenoxy chlorophenoxy)pyridin-3-yl4-chloro-3- pentafluorophenyl 429 methylphenoxy 4-chloro-2-3,4-dimethoxyphenyl 467 cyclohexylphenoxy 4-chloro-2-2-(trifluoromethyl)phenyl 475 cyclohexylphenoxy 4-chloro-2-2,4-difluorophenyl 443 cyclohexylphenoxy 4-chloro-2-3-(trifluoromethyl)phenyl 475 cyclohexylphenoxy 4-chloro-2- 2-naphthyl457 cyclohexylphenoxy 4-chloro-2- 2-methoxyphenyl 437 cyclohexylphenoxy4-chloro-2- 3,4,5-trimethylphenyl 497 cyclohexylphenoxy 4-chloro-2-3,4-dichlorophenyl 176 cyclohexylphenoxy 4-chloro-2- 3-bromophenyl 486cyclohexylphenoxy 4-chloro-2- 3-pyridyl 408 cyclohexylphenoxy4-chloro-2- 2-ethoxynaphth-1-yl 501 cyclohexylphenoxy 4-chloro-2-2,3-dichlorophenyl 476 cyclohexylphenoxy 4-chloro-2- 6-chloropyrid-3-yl442 cyclohexylphenoxy 4-chloro-2- 4-(trifluoromethoxy)phenyl 491cyclohexylphenoxy 4-chloro-2- 2-fluoro-4- 493 cyclohexylphenoxy(trifluoromethyl)phenyl 4-chloro-2- 3-bromothienyl 492 cyclohexylphenoxy4-chloro-2- 2-acetoxyphenyl 465 cyclohexylphenoxy 4-chloro-2-5-methylisoxazol-3-yl 412 cyclohexylphenoxy 4-chloro-2-2-(phenylthio)pyrid-3-yl 516 cyclohexylphenoxy 4-chloro-2-2-(trifluoromethoxy)phenyl 491 cyclohexylphenoxy 4-chloro-2-1-phenyl-5-propylpyrazin 515 cyclohexylphenoxy 4-yl 4-chloro-2-2-ethoxyphenyl 451 cyclohexylphenoxy 4-chloro-2- 3-chlorothien-2-yl 447cyclohexylphenoxy 4-chloro-2- 1-(2-(2-methyl)propyl)-3- 467cyclohexylphenoxy methylpyrazol-5-yl 4-chloro-2- 3,5-dichlorophenyl 476cyclohexylphenoxy 4-chloro-2- 2-(propylthio)pyridin-3-yl 482cyclohexylphenoxy 4-chloro-2- 2-(ethylthio)pyridin-3-yl 468cyclohexylphenoxy 4-chloro-2- 3-bromopyridin-5-yl 487 cyclohexylphenoxy4-chloro-2- 4-methyl-1,2,3-thiadiazol- 429 cyclohexylphenoxy 5-yl4-chloro-2- 1-methyl-3-(2-(2- 467 cyclohexylphenoxymethyl)propyl)pyrazol-5-yl 4-chloro-2- 3-chlorobenzo[b]thiophen- 497cyclohexylphenoxy 2-yl 4-chloro-2- 4-chlorophenyl 441 cyclohexylphenoxy4-chloro-2- 4-methyl-2-phenyl-1,2,3- 488 cyclohexylphenoxy triazol-5-yl4-chloro-2- benzo[b]thiophen-2-yl 463 cyclohexylphenoxy 4-chloro-2-3,4-dimethylphenyl 435 cyclohexylphenoxy 4-chloro-2-2-(phenoxy)pyridin-3-yl 500 cyclohexylphenoxy 4-chloro-2-2-(methylthio)pyridin-3-yl 454 cyclohexylphenoxy 4-chloro-2-5-methyl-3-phenylisoxazol- 488 cyclohexylphenoxy 4-yl 4-chloro-2-4-chloro-1,3-dimethyl 510 cyclohexylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-2- 2-chloro-6-methylpyridin- 456 cyclohexylphenoxy 4-yl4-chloro-2- 3,5-dimethylisoxazol-4-yl 426 cyclohexylphenoxy 4-chloro-2-1-naphthyl 457 cyclohexylphenoxy 4-chloro-2- 2-fluorophenyl 425cyclohexylphenoxy 4-chloro-2- 4-propylphenyl 449 cyclohexylphenoxy4-chloro-2- 3-fluorophenyl 425 cyclohexylphenoxy 4-chloro-2-2,6-difluorophenyl 443 cyclohexylphenoxy 4-chloro-2- 2-chlorophenyl 441cyclohexylphenoxy 4-chloro-2- 3-(chloromethyl)phenyl 455cyclohexylphenoxy 4-chloro-2- 4-(2-(2- 463 cyclohexylphenoxymethyl)propyl)phenyl 4-chloro-2- 3-chlorophenyl 441 cyclohexylphenoxy4-chloro-2- 3,5-dimethoxyphenyl 467 cyclohexylphenoxy 4-chloro-2-2,6-dichlorophenyl 476 cyclohexylphenoxy 4-chloro-2- 2,4-dichlorophenyl476 cyclohexylphenoxy 4-chloro-2- 4-fluorophenyl 425 cyclohexylphenoxy4-chloro-2- 4-butylphenyl 463 cyclohexylphenoxy 4-chloro-2-2-methylphenyl 421 cyclohexylphenoxy 4-chloro-2- phenyl 407cyclohexylphenoxy 4-chloro-2- 4-ethylphenyl 435 cyclohexylphenoxy4-chloro-2- 2,3-difluorophenyl 443 cyclohexylphenoxy 4-chloro-2-2,6-dimethoxyphenyl 467 cyclohexylphenoxy 4-chloro-2- 3,4-difluorophenyl443 cyclohexylphenoxy 4-chloro-2- 2,5-difluorophenyl 443cyclohexylphenoxy 4-chloro-2- 4-ethoxyphenyl 451 cyclohexylphenoxy4-chloro-2- 2,4,6-trichlorophenyl 510 cyclohexylphenoxy 4-chloro-2-3-methylphenyl 421 cyclohexylphenoxy 4-chloro-2- 2-fluoro-5- 493cyclohexylphenoxy (trifluoromethyl)phenyl 4-chloro-2- 3-methoxyphenyl437 cyclohexylphenoxy 4-chloro-2- 2-bromophenyl 486 cyclohexylphenoxy4-chloro-2- 4-bromophenyl 486 cyclohexylphenoxy 4-chloro-2- 4-fluoro-3-493 cyclohexylphenoxy (trifluoromethyl)phenyl 4-chloro-2-3-(trifluoromethoxy)phenyl 491 cyclohexylphenoxy 4-chloro-2-9-fluorenon-4-yl 503 cyclohexylphenoxy 4-chloro-2- isoxazol-5-yl 398cyclohexylphenoxy 4-chloro-2- benzofuroxan-5-yl 465 cyclohexylphenoxy4-chloro-2- 2-chloropyrid-3-yl 442 cyclohexylphenoxy 4-chloro-2- 2-(4-514 cyclohexylphenoxy methylphenoxy)pyridin-3-yl 4-chloro-2-pyridin-4-yl 408 cyclohexylphenoxy 4-chloro-2- anthraquinon-2-yl 537cyclohexylphenoxy 4-chloro-2- 2-iodophenyl 533 cyclohexylphenoxy4-chloro-2- 4-pentylphenyl 477 cyclohexylphenoxy 4-chloro-2-2-(4-chlorophenylthio) 550 cyclohexylphenoxy pyridin-3-yl 4-chloro-2-2,6-dimethylphenyl 435 cyclohexylphenoxy 4-chloro-2- 2,5-dimethoxyphenyl467 cyclohexylphenoxy 4-chloro-2- 2,5-dichloropyridin-3-yl 477cyclohexylphenoxy 4-chloro-2- 2-chloro-6-methoxypyridin- 472cyclohexylphenoxy 4-yl 4-chloro-2- 2,3-dichloropyridin-5-yl 477cyclohexylphenoxy 4-chloro-2- 1-naphthyl 471 cyclohexylphenoxy4-chloro-2- 2,4-dimethoxyphenyl 467 cyclohexylphenoxy 4-chloro-2- 3,5-546 cyclohexylphenoxy bis(trifluoromethyl)phenyl 4-chloro-2- 2-(4- 534cyclohexylphenoxy chlorophenoxy)pyridin-3-yl 4-chloro-2-pentafluorophenyl 497 cyclohexylphenoxy 4-chloro-3,5-3,4-dimethoxyphenyl 413 dimethylphenoxy 4-chloro-3,5-2-(trifluoromethyl-)phenyl 421 dimethylphenoxy 4-chloro-3,5-2,4-difluorophenyl 389 dimethylphenoxy 4-chloro-3,5-3-(trifluoromethyl)phenyl 421 dimethylphenoxy 4-chloro-3,5- 2-naphthyl403 dimethylphenoxy 4-chloro-3,5- 2-methoxyphenyl 484 dimethylphenoxy4-chloro-3,5- 3,4,5-trimethylphenyl 443 dimethylphenoxy 4-chloro-3,5-3,4-dichlorophenyl 422 dimethylphenoxy 4-chloro-3,5- 3-bromophenyl 432dimethylphenoxy 4-chloro-3,5- 3-pyridyl 354 dimethylphenoxy4-chloro-3,5- 2-ethoxynaphth-1-yl 447 dimethylphenoxy 4-chloro-3,5-2,3-dichlorophenyl 422 dimethylphenoxy 4-chloro-3,5- 6-chloropyrid-3-yl388 dimethylphenoxy 4-chloro-3,5- 4-(trifluoromethoxy)phenyl 437dimethylphenoxy 4-chloro-3,5- 2-fluoro-4- 439 dimethylphenoxy(trifluoromethyl)phenyl 4-chloro-3,5- 3-bromothienyl 438 dimethylphenoxy4-chloro-3,5- 2-acetoxyphenyl 411 dimethylphenoxy 4-chloro-3,5-5-methylisoxazol-3-yl 358 dimethylphenoxy 4-chloro-3,5-2-(phenylthio)pyrid-3-yl 462 dimethylphenoxy 4-chloro-3,5-2-(trifluoromethoxy)phenyl 437 dimethylphenoxy 4-chloro-3,5-1-phenyl-5-propylpyrazin- 461 dimethylphenoxy 4-yl 4-chloro-3,5-2-ethoxyphenyl 397 dimethylphenoxy 4-chloro-3,5- 3-chlorothien-2-yl 393dimethylphenoxy 4-chloro-3,5- 1-(2-(2-methyl)propyl)-3- 413dimethylphenoxy methylpyrazol-5-yl 4-chloro-3,5- 3,5-dichlorophenyl 422dimethylphenoxy 4-chloro-3,5- 2-(propylthio)pyridin-3-yl 428dimethylphenoxy 4-chloro-3,5- 2-(ethylthio)pyridin-3-yl 414dimethylphenoxy 4-chloro-3,5- 3-bromopyridin-5-yl 433 dimethylphenoxy4-chloro-3,5- 4-methyl-1,2,3-thiadiazol 375 dimethylphenoxy 5-yl4-chloro-3,5- 1-methyl-3-(2-(2- 413 dimethylphenoxymethyl)propyl)pyrazol-5-yl- 4-chloro-3,5- 3-chlorobenzo[b]thiophen- 443dimethylphenoxy 2-yl 4-chloro-3,5- 4-chlorophenyl 387 dimethylphenoxy4-chloro-3,5- 4-methyl-2-phenyl-1,2,3- 434 dimethylphenoxy triazol-5-yl4-chloro-3,5- benzo[b]thiophen-2-yl 409 dimethylphenoxy 4-chloro-3,5-3,4-dimethylphenyl 381 dimethylphenoxy 4-chloro-3,5-2-(phenoxy)pyridin-3-yl 446 dimethylphenoxy 4-chloro-3,5-2-(methylthio)pyridin-3-yl 400 dimethylphenoxy 4-chloro-3,5-5-methyl-3-phenylisoxazol- 434 dimethylphenoxy 4-yl 4-chloro-35-4-chloro-1,3-dimethyl 456 dimethylphenoxy pyrazolo[3,4-b]pyridin-3- yl4-chloro-3,5- 2-chloro-6-methylpyridin 402 dimethylphenoxy 4-yl4-chloro-3,5- 3,5-dimethylisoxazol-4-yl 372 dimethylphenoxy4-chloro-3,5- 1-naphthyl 403 dimethylphenoxy 4-chloro-3,5-2-fluorophenyl 371 dimethylphenoxy 4-chloro-3,5- 4-propylphenyl 395dimethylphenoxy 4-chloro-3,5- 3-fluorophenyl 371 dimethylphenoxy4-chloro-3,5- 2,6-difluorophenyl 389 dimethylphenoxy 4-chloro-3,5-2-chlorophenyl 387 dimethylphenoxy 4-chloro-3,5- 3-(chloromethyl)phenyl401 dimethylphenoxy 4-chloro-3,5- 4-(2-(2- 409 dimethylphenoxymethyl)propyl)phenyl 4-chloro-3,5- 3-chlorophenyl 387 dimethylphenoxy4-chloro-3,5- 3,5-dimethoxyphenyl 413 dimethylphenoxy 4-chloro-3,5-2,6-dichlorophenyl 422 dimethylphenoxy 4-chloro-3,5- 2,4-dichlorophenyl422 dimethylphenoxy 4-chloro-3,5- 4-fluorophenyl 371 dimethylphenoxy4-chloro-3,5- 4-butylphenyl 409 dimethylphenoxy 4-chloro-3,5-2-methyl-phenyl 367 dimethylphenoxy 4-chloro-3,5- phenyl 353dimethylphenoxy 4-chloro-3,5- 4-ethylphenyl 381 dimethylphenoxy4-chloro-3,5- 2,3-difluorophenyl 389 dimethylphenoxy 4-chloro-3,5-2,6-dimethoxyphenyl 413 dimethylphenoxy 4-chloro-3,5- 3,4-difluorophenyl389 dimethylphenoxy 4-chloro-3,5- 2,5-difluorophenyl 389 dimethylphenoxy4-chloro-3,5- 4-ethoxyphenyl 397 dimethylphenoxy 4-chloro-3,5-2,4,6-trichlorophenyl 456 dimethylphenoxy 4-chloro-3,5- 3-methylphenyl367 dimethylphenoxy 4-chloro-3,5- 2-fluoro-5- 439 dimethylphenoxy(trifluorophenyl)phenyl 4-chloro-3,5- 3-methoxyphenyl 383dimethylphenoxy 4-chloro-3,5- 2-bromophenyl 432 dimethylphenoxy4-chloro-3,5- 4-bromophenyl 432 dimethylphenoxy 4-chloro-3,5-4-fluoro-3- 439 dimethylphenoxy (trifluoromethyl-)phenyl 4-chloro-3,5-3-(trifluoromethoxy)phenyl 437 dimethyl-phenoxy 4-chloro-3,5-9-fluorenon-4-yl 455 dimethylphenoxy 4-chloro-3,5- isoxazol-5-yl 344dimethylphenoxy 4-chloro-3,5- benzofuroxan-5-yl 411 dimethylphenoxy4-chloro-3,5- 2-chloropyrid-3-yl 388 dimethyl-phenoxy 4-chloro-3,5-2-(4- 460 dimethylphenoxy methylphenoxy)pyridin-3-yl 4-chloro-3,5-pyridin-4-yl 354 dimethylphenoxy 4-chloro-3,5- anthraquinon-2-yl 483dimethylphenoxy 4-chloro-3,5- 2-iodophenyl 479 dimethylphenoxy4-chloro-3,5- 4-pentylphenyl 423 dimethylphenoxy 4-chloro-3,5-2-(4-chlorophenylthio) 496 dimethylphenoxy pyridin-3-yl 4-chloro-3,5-2,6-dimethylphenyl 381 dimethylphenoxy 4-chloro-3,5- 2,5-dimethoxyphenyl413 dimethylphenoxy 4-chloro-3,5 2,5-dichloropyridin-3-yl 423dimethylphenoxy 4-chloro-3,5- 2-chloro-6-methoxypyridin- 418dimethylphenoxy 4-yl 4-chloro-3,5- 2,3-dichloropyridin-5-yl 423dimethylphenoxy 4-chloro-3,5- 1-naphthyl 417 dimethylphenoxy4-chloro-3,5- 2,4-dimethoxyphenyl 413 dimethylphenoxy 4-chloro-3,5- 3,5-489 dimethylphenoxy bis(trifluoromethyl)phenyl 4-chloro-3,5- 2-(4- 480dimethylphenoxy chlorophenoxy)pyridin-3-yl 4-chloro-3,5-pentafluorophenyl 443 dimethylphenoxy pyrid-3-yloxy 3,4-dimethoxyphenyl351 pyrid-3-yloxy 2-(trifluoromethyl)phenyl 359 pyrid-3-yloxy2,4-difluorophenyl 327 pyrid-3-yloxy 3-(trifluoromethyl)phenyl 359pyrid-3-yloxy 2-naphthyl 341 pyrid-3-yloxy 2-methoxyphenyl 321pyrid-3-yloxy 3,4,5-trimethylphenyl 381 pyrid-3-yloxy 3,4-dichlorophenyl360 pyrid-3-yloxy 3-bromophenyl 370 pyrid-3-yloxy 3-pyridyl 292pyrid-3-yloxy 2-ethoxynaphth-1-yl 385 pyrid-3-yloxy 2,3-dichlorophenyl360 pyrid-3-yloxy 6-chloropyrid-3-yl 327 pyrid-3-yloxy4-(trifluoromethoxy)phenyl 375 pyrid-3-yloxy 2-fluoro-4- 377(trifluoromethyl)phenyl pyrid-3-yloxy 3-bromothienyl 376 pyrid-3-yloxy2-acetoxyphenyl 349 pyrid-3-yloxy 5-methylisoxazol-3-yl 296pyrid-3-yloxy 2-(phenylthio)pyrid-3-yl 400 pyrid-3-yloxy2-(trifluoromethoxy)phenyl 375 pyrid-3-yloxy 1-phenyl-5-propylpyrazin-399 4-yl pyrid-3-yloxy 2-ethoxyphenyl 335 pyrid-3-yloxy3-chlorothien-2-yl 332 pyrid-3-yloxy 1-(2-(2-methyl)propyl)-3- 351methylpyrazol-5-yl pyrid-3-yloxy 3,5-dichlorophenyl 360 pyrid-3-yloxy2-(propylthio)pyridin-3-yl 366 pyrid-3-yloxy 2-(ethylthio)pyridin-3-yl352 pyrid-3-yloxy 3-bromopyridin-5-yl 371 pyrid-3-yloxy4-methyl-1,2,3-thiadiazol- 313 5-yl pyrid-3-yloxy 1-methyl-3-(2-(2- 351methyl)propyl)pyrazol-5-yl pyrid-3-yloxy 3-chlorobenzo [bi thiophen- 3822-yl pyrid-3-yloxy 4-chlorophenyl 326 pyrid-3-yloxy4-methyl-2-phenyl-1,2,3- 372 triazol-5-yl pyrid-3-yloxy benzo[b]thiophen-2-yl 347 pyrid-3-yloxy 3,4-dimethylphenyl 319 pyrid-3-yloxy2-(phenoxy)pyridin-3-yl 384 pyrid-3-yloxy 2-(methylthio)pyridin-3-yl 338pyrid-3-yloxy 5-methyl-3-phenylisoxazol- 372 4-yl pyrid-3-yloxy4-chloro-1,3-dimethyl 395 pyrazolo[3,4-b]pyridin-3- yl pyrid-3-yloxy2-chloro-6-methylpyridin- 341 4-yl pyrid-3-yloxy3,5-dimethylisoxazol-4-yl 310 pyrid-3-yloxy 1-naphthyl 341 pyrid-3-yloxy2-fluorophenyl 309 pyrid-3-yloxy 4-propylphenyl 333 pyrid-3-yloxy3-fluorophenyl 309 pyrid-3-yloxy 2,6-difluorophenyl 327 pyrid-3-yloxy2-chlorophenyl 326 pyrid-3-yloxy 3-(chloromethyl)phenyl 340pyrid-3-yloxy 4-(2-(2- 347 methyl)propyl)phenyl pyrid-3-yloxy3-chlorophenyl 326 pyrid-3-yloxy 3,5-dimethoxyphenyl 351 pyrid-3-yloxy2,6-dichlorophenyl 360 pyrid-3-yloxy 2,4-dichlorophenyl 360pyrid-3-yloxy 4-fluorophenyl 309 pyrid-3-yloxy 4-butylphenyl 347pyrid-3-yloxy 2-methylphenyl 305 pyrid-3-yloxy phenyl 291 pyrid-3-yloxy4-ethylphenyl 319 pyrid-3-yloxy 2,3-difluorophenyl 327 pyrid-3-yloxy2,6-dimethoxyphenyl 351 pyrid-3-yloxy 3,4-difluorophenyl 327pyrid-3-yloxy 2,5-difluorophenyl 327 pyrid-3-yloxy 4-ethoxyphenyl 335pyrid-3-yloxy 2,4,6-trichlorophenyl 395 pyrid-3-yloxy 3-methylphenyl 305pyrid-3-yloxy 2-fluoro-5- 377 (trifluoromethyl)phenyl pyrid-3-yloxy3-methoxyphenyl 321 pyrid-3-yloxy 2-bromophenyl 370 pyrid-3-yloxy4-bromophenyl 370 pyrid-3-yloxy 4-fluoro-3- 377 (trifluoromethyl)phenylpyrid-3-yloxy 3-(trifluoromethoxy)phenyl 375 pyrid-3-yloxy9-fluorenon-4-yl 393 pyrid-3-yloxy isoxazol-5-yl 282 pyrid-3-yloxybenzofuroxan-5-yl 349 pyrid-3-yloxy 2-chloropyrid-3-yl 327 pyrid-3-yloxy2-(4- 398 methylphenoxy)pyridin-3-yl pyrid-3-yloxy pyridin-4-yl 292pyrid-3-yloxy anthraquinon-2-yl 421 pyrid-3-yloxy 2-iodophenyl 417pyrid-3-yloxy 4-pentylphenyl 361 pyrid-3-yloxy 2-(4-chlorophenylthio)435 pyridin-3-yl pyrid-3-yloxy 2,6-dimethylphenyl 319 pyrid-3-yloxy2,5-dimethoxyphenyl 354 pyrid-3-yloxy 2,5-dichloropyridin-3-yl- 361pyrid-3-yloxy 2-chloro-6-methoxypyridin- 357 4-yl pyrid-3-yloxy2,3-dichloropyridin-5-yl 361 pyrid-3-yloxy 1-naphthyl 355 pyrid-3-yloxy2,4-dimethoxyphenyl 351 pyrid-3-yloxy 3,5- 427bis(trifluoromethyl)phenyl pyrid-3-yloxy 2-(4- 419chlorophenoxy)pyridin-3-yl pyrid-3-yloxy pentafluorophenyl 3814-bromophenoxy 3,4-dimethoxyphenyl 429 4-bromophenoxy2-(trifluoromethyl)phenyl 437 4-bromophenoxy 2,4-difluorophenyl 4054-bromophenoxy 3-(trifluoromethyl)phenyl 437 4-bromophenoxy 2-naphthyl419 4-bromophenoxy 2-methoxyphenyl 399 4-bromophenoxy3,4,5-trimethylphenyl 459 4-bromophenoxy 3,4-dichlorophenyl 4384-bromophenoxy 3-bromophenyl 448 4-bromophenoxy 3-pyridyl 3704-bromophenoxy 2-ethoxynaphth-1-yl 463 4-bromophenoxy 2,3-dichlorophenyl438 4-bromophenoxy 6-chloropyrid-3-yl 405 4-bromophenoxy4-(trifluoromethoxy)phenyl 453 4-bromophenoxy 2-fluoro-4- 455(trifluoromethyl)phenyl 4-bromophenoxy 3-bromothienyl 454 4-bromophenoxy2-acetoxyphenyl 427 4-bromophenoxy 5-methylisoxazol-3-yl 3744-bromophenoxy 2-(phenylthio)pyrid-3-yl 478 4-bromophenoxy2-(trifluoromethoxy)phenyl 453 4-bromophenoxy 1-phenyl-5-propylpyrazin-477 4-yl 4-bromophenoxy 2-ethoxyphenyl 413 4-bromophenoxy3-chlorothien-2-yl 410 4-bromophenoxy 1-(2-(2-methyl)propyl)-3- 429methylpyrazol-5-yl 4-bromophenoxy 3,5-dichlorophenyl 438 4-bromophenoxy2-(propylthio)pyridin-3-yl 444 4-bromophenoxy 2-(ethylthio)pyridin-3-yl430 4-bromophenoxy 3-bromopyridin-5-yl 449 4-bromophenoxy4-methyl-1,2,3-thiadiazol- 391 5-yl 4-bromophenoxy 1-methyl-3-(2-(2- 429methyl)propyl)pyrazol-5-yl 4-bromophenoxy 3-chlorobenzo[b]thiophen- 4602-yl 4-bromophenoxy 4-chlorophenyl 404 4-bromophenoxy4-methyl-2-phenyl-1,2,3- 450 triazol-5-yl 4-bromophenoxybenzo[b]thiophen-2-yl 425 4-bromophenoxy 3,4-dimethylphenyl 3974-bromophenoxy 2-(phenoxy)pyridin-3-yl 462 4-bromophenoxy2-(methylthio)pyridin-3-yl 416 4-bromophenoxy 5-methyl-3-phenylisoxazol-450 4-yl 4-bromophenoxy 4-chloro-1,3-dimethyl 473pyrazolo[3,4-b]pyridin-3- yl 4-bromophenoxy 2-chloro-6-methylpyridin-419 4-yl 4-bromophenoxy 3,5-dimethylisoxazol-4-yl 388 4-bromophenoxy1-naphthyl 419 4-bromophenoxy 2-fluorophenyl 387 4-bromophenoxy4-propylphenyl 411 4-bromophenoxy 3-fluorophenyl 387 4-bromophenoxy2,6-difluorophenyl 405 4-bromophenoxy 2-chlorophenyl 414 4-bromophenoxy3-(chloromethyl)phenyl 418 4-bromophenoxy 4-(2-(2- 425methyl)propyl)phenyl 4-bromophenoxy 3-chlorophenyl 404 4-bromophenoxy3,5-dimethoxyphenyl 429 4-bromophenoxy 2,6-dichlorophenyl 4384-bromophenoxy 2,4-dichlorophenyl 438 4-bromophenoxy 4-fluorophenyl 3874-bromophenoxy 4-butylphenyl 425 4-bromophenoxy 2-methylphenyl 3834-bromophenoxy phenyl 369 4-bromophenoxy 4-ethylphenyl 3974-bromophenoxy 2,3-difluorophenyl 405 4-bromophenoxy 2,6-dimethoxyphenyl429 4-bromophenoxy 3,4-difluorophenyl 405 4-bromophenoxy2,5-difluorophenyl 405 4-bromophenoxy 4-ethoxyphenyl 413 4-bromophenoxy2,4,6-trichlorophenyl 473 4-bromophenoxy 3-methylphenyl 3834-bromophenoxy 2-fluoro-5- 455 (trifluoromethyl)phenyl 4-bromophenoxy3-methoxyphenyl 399 4-bromophenoxy 2-bromophenyl 448 4-bromophenoxy4-bromophenyl 448 4-bromophenoxy 4-fluoro-3- 455 (trifluoromethyl)phenyl4-bromophenoxy 3-(trifluoromethoxy)phenyl 453 4-bromophenoxy9-fluorenon-4-yl 471 4-bromophenoxy isoxazol-5-yl 360 4-bromophenoxybenzo furoxan-5-yl 427 4-bromophenoxy 2-chloropyrid-3-yl 3604-bromophenoxy 2-(4- 476 methylphenoxy)pyridin-3-yl 4-bromophenoxypyridin-4-yl 370 4-bromophenoxy anthraquinon-2-yl 499 4-bromophenoxy2-iodophenyl 495 4-bromophenoxy 4-pentylphenyl 439 4-bromophenoxy 2-(4-513 chlorophenylthio)pyridin- 3-yl 4-bromophenoxy 2,6-dimethylphenyl 3974-bromophenoxy 2,5-dimethoxyphenyl 429 4-bromophenoxy2,5-dichloropyridin-3-yl 439 4-bromophenoxy 2-chloro-6-methoxypyridin-435 4-yl 4-bromophenoxy 2,3-dichloropyridin-5-yl 439 4-bromophenoxy1-naphthyl 433 4-bromophenoxy 2,4-dimethoxyphenyl 429 4-bromophenoxy3,5- 505 bis(trifluoromethyl)phenyl 4-bromophenoxy 2-(4- 497chlorophenoxy)pyridin-3-yl 4-bromophenoxy pentafluorophenyl 4594-chloro-2- 4-biphenyl 431 methylphenylthio 4-chloro-2-3,4-dimethoxyphenyl 415 methylphenylthio 4-chloro-2-2-(trifluoromethyl)phenyl 423 methylphenylthio 4-chloro-2-2,4-difluorophenyl 391 methylphenylthio 4-chloro-2- 4-cyanophenyl 380methylphenylthio 4-chloro-2- 3-(trifluoromethyl)phenyl 423methylphenylthio 4-chloro-2- 3-cyanophenyl 380 methylphenylthio4-chloro-2- 2-naphthyl 405 methylphenylthio 4-chloro-2- 2-methoxyphenyl385 methylphenylthio 4-chloro-2- 3,4,5-trimethylphenyl 445methylphenylthio 4-chloro-2- 4-nitrophenyl 400 methylphenylthio4-chloro-2- 3,4-dichlorophenyl 424 methylphenylthio 4-chloro-2-5-nitrofuran-2-yl 390 methylphenylthio 4-chloro-2- 3-bromophenyl 434methylphenylthio 4-chloro-2- 3-pyridyl 356 methylphenylthio 4-chloro-2-2-ethoxynaphth-1-yl 449 methylphenylthio 4-chloro-2- 2,3-dichlorophenyl424 methylphenylthio 4-chloro-2- 3-nitrophenyl 400 methylphenylthio4-chloro-2- 6-chloropyrid-3-yl 390 methylphenylthio 4-chloro-2-4-(trifluoromethoxy)phenyl 439 methylphenylthio 4-chloro-2- 2-fluoro-4-441 methylphenylthio (trifluoromethyl)phenyl 4-chloro-2- 3-bromothienyl440 methylphenylthio 4-chloro-2- 2-acetoxyphenyl 413 methylphenylthio4-chloro-2- 5-methylisoxazol-3-yl 360 methylphenylthio 4-chloro-2-2-(phenylthio)pyrid-3-yl 464 methylphenyl thio 4-chloro-2-2-(trifluoromethoxy)phenyl 439 methylphenylthio 4-chloro-2-1-phenyl-5-propylpyrazin- 463 methylphenylthio 4-yl 4-chloro-2-2-ethoxyphenyl 399 methylphenylthio 4-chloro-2- 3-chlorothien-2-yl 395methylphenylthio 4-chloro-2- 1-(2-(2-methyl)propyl)-3- 415methylphenylthio methylpyrazol-5-yl 4-chloro-2- 3,5-dichlorophenyl 424methylphenylthio 4-chloro-2- 2-(propylthio)pyridin-3-yl 430methylphenylthio 4-chloro-2- 2-(ethylthio)pyridin-3-yl 416methylphenylthio 4-chloro-2- 3-bromopyridin-5-yl 435 methylphenylthio4-chloro-2- 4-methyl-1,2,3-thiadiazol- 377 methylphenylthio 5-yl4-chloro-2- 1-methyl-3-(2-(2- 415 methylphenylthiomethyl)propyl)pyrazol-5-yl 4-chloro-2- 3-chlorobenzo[b]thiophen- 445methylphenylthio 2-yl 4-chloro-2- 4-chlorophenyl 389 methylphenylthio4-chloro-2- 4-methyl-2-phenyl-1,2,3- 436 methylphenylthio triazol-5-yl4-chloro-2- benzo[b]thiophen-2-yl 411 methylphenylthio 4-chloro-2-3,4-dimethylphenyl 383 methylphenylthio 4-chloro-2-2-(phenoxy)pyridin-3-yl 448 methylphenylthio 4-chloro-2-2-(methylthio)pyridin-3-yl 402 methylphenylthio 4-chloro-2-5-methyl-3-phenylisoxazol- 436 methylphenylthio 4-yl 4-chloro-2-4-chloro-1,3-dimethyl 458 methylphenylthio pyrazolo[3,4-b]pyridin-3-4-yl 4-chloro-2- 2-chloro-6-methylpyridin- 404 methylphenylthio 4-yl4-chloro-2- 3,5-dimethylisoxazol-4-yl 374 methylphenylthio 4-chloro-2-1-naphthyl 405 methylphenylthio 4-chloro-2- 2-fluorophenyl 373methylphenylthio 4-chloro-2- 4-propylphenyl 397 methylphenylthio4-chloro-2- 4-(trifluoromethyl)phenyl 423 methylphenylthio 4-chloro-2-3-fluorophenyl 373 methylphenylthio 4-chloro-2- 2,6-difluorophenyl 391methylphenylthio 4-chloro-2- 2-chlorophenyl 389 methylphenylthio4-chloro-2- 3-(chloromethyl)phenyl 403 methylphenylthio 4-chloro-2-4-(2-(2- 411 methylphenylthio methyl)propyl)phenyl 4-chloro-2-3-chlorophenyl 389 methylphenylthio 4-chloro-2- 2-nitrophenyl 400methylphenylthio 4-chloro-2- 3,5-dimethoxyphenyl 415 methylphenylthio4-chloro-2- 2,6-dichlorophenyl 424 methylphenylthio 4-chloro-2-2,4-dichlorophenyl 424 methylphenylthio 4-chloro-2- 4-fluorophenyl 373methylphenylthio 4-chloro-2- 4-butylphenyl 411 methylphenylthio4-chloro-2- 2-methylphenyl 369 methylphenylthio 4-chloro-2- phenyl 355methylphenylthio 4-chloro-2- 4-ethylphenyl 383 methylphenylthio4-chloro-2- 2,3-difluorophenyl 391 methylphenylthio 4-chloro-2-2,6-dimethoxyphenyl 415 methylphenylthio 4-chloro-2- 3,4-difluorophenyl391 methylphenylthio 4-chloro-2- 2,5-difluorophenyl 391 methylphenylthio4-chloro-2- 4-ethoxyphenyl 399 methylphenylthio 4-chloro-2-2,4,6-trichlorophenyl 458 methylphenylthio 4-chloro-2- 3-methylphenyl369 methylphenylthio 4-chloro-2- 2-fluoro-5- 441 methylphenylthio(trifluoromethyl)phenyl 4-chloro-2- 3-methoxyphenyl 385 methylphenylthio4-chloro-2- thien-2-yl 361 methylphenylthio 4-chloro-2- 2-bromophenyl434 methylphenylthio 4-chloro-2- 4-bromophenyl 434 methylphenylthio4-chloro-2- 4-fluoro-3- 441 methylphenylthio (trifluoromethyl)phenyl4-chloro-2- 3-(trifluoromethoxy)phenyl 439 methylphenylthio 4-chloro-2-9-fluorenon-4-yl 457 methylphenylthio 4-chloro-2- isoxazol-5-yl 346methylphenylthio 4-chloro-2- benzofuroxan-5-yl 413 methylphenylthio4-chloro-2- 2-chloropyrid-3-yl 390 methylphenylthio 4-chloro-2-3,5-difluorophenyl 391 methylphenylthio 4-chloro-2- 2-(4- 462methylphenylthio methylphenoxy)pyridin-3-yl 4-chloro-2- pyridin-4-yl 356methylphenylthio 4-chloro-2- anthraquinon-2-yl 485 methylphenylthio4-chloro-2- 2-iodophenyl 481 methylphenylthio 4-chloro-2- 4-biphenyl 414methylanilino 4-chloro-2- 3,4-dimethoxyphenyl 398 methylanilino4-chloro-2- 2-(trifluoromethyl)phenyl 406 methylanilino 4-chloro-2-2,4-difluorophenyl 374 methylanilino 4-chloro-2- 4-cyanophenyl 363methylanilino 4-chloro-2- 3-(trifluoromethyl)phenyl 406 methylanilino4-chloro-2- 3-cyanophenyl 363 methylanilino 4-chloro-2- 2-naphthyl 388methylanilino 4-chloro-2- 2-methoxyphenyl 368 methylanilino 4-chloro-2-3,4,5-trimethylphenyl 428 methylanilino 4-chloro-2- 4-nitrophenyl 383methylanilino 4-chloro-2- 3,4-dichlorophenyl 407 methylanilino4-chloro-2- 5-nitrofuran-2-yl 373 methylanilino 4-chloro-2-3-bromophenyl 417 methylanilino 4-chloro-2- 3-pyridyl 339 methylanilino4-chloro-2- 2-ethoxynaphth-1-yl 432 methylanilino 4-chloro-2-2,3-dichlorophenyl 407 methylanilino 4-chloro-2- 3-nitrophenyl 383methylanilino 4-chloro-2- 6-chloropyrid-3-yl 373 methylanilino4-chloro-2- 4-(trifluoromethoxy)phenyl 422 methylanilino 4-chloro-2-2-fluoro-4- 424 methylanilino (trifluoromethyl)phenyl 4-chloro-2-3-bromothienyl 423 methylanilino 4-chloro-2- 2-acetoxyphenyl 396methylanilino 4-chloro-2- 5-methylisoxazol-3-yl 343 methylanilino4-chloro-2- 2-(phenylthio)pyrid-3-yl 447 methylanilino 4-chloro-2-2-(trifluoromethoxy)phenyl 422 methylanilino 4-chloro-2-1-phenyl-5-propylpyrazin- 446 methylanilino 4-yl 4-chloro-2-2-ethoxyphenyl 382 methylanilino 4-chloro-2- 3-chlorothien-2-yl 378methylanilino 4-chloro-2- 1-(2-(2-methyl)propyl)-3- 398 methylanilinomethylpyrazol-5-yl 4-chloro-2- 3,5-dichlorophenyl 407 methylanilino4-chloro-2- 2-(propylthio)pyridin-3-yl 413 methylanilino 4-chloro-2-2-(ethylthio)pyridin-3-yl 399 methylanilino 4-chloro-2-3-bromopyridin-5-yl 418 methylanilino 4-chloro-2-4-methyl-1,2,3-thiadiazol- 360 methylanilino 5-yl 4-chloro-2-1-methyl-3-(2-(2- 398 methylanilino methyl)propyl)pyrazol-5-yl4-chloro-2- 3-chlorobenzo[b]thiophen- 428 methylanilino 2-yl 4-chloro-2-4-chlorophenyl 372 methylanilino 4-chloro-2- 4-methyl-2-phenyl-1,2,3-419 methylanilino triazol-5-yl 4-chloro-2- benzo[b]thiophen-2-yl 394methylanilino 4-chloro-2- 3,4-dimethylphenyl 366 methylanilino4-chloro-2- 2-(phenoxy)pyridin-3-yl 431 methylanilino 4-chloro-2-2-(methylthio)pyridin-3-yl 385 methylanilino 4-chloro-2-5-methyl-3-phenylisoxazol- 419 methylanilino 4-yl 4-chloro-2-4-chloro-1,3-dimethyl 441 methylanilino pyrazolo [3,4-b]pyridin-3- yl4-chloro-2- 2-chloro-6-methylpyridin- 387 methylanilino 4-yl 4-chloro-2-3,5-dimethylisoxazol-4-yl 357 methylanilino 4-chloro-2- 1-naphthyl 388methylanilino 4-chloro-2- 2-fluorophenyl 356 methylanilino 4-chloro-2-4-propylphenyl 380 methylanilino 4-chloro-2- 4-(trifluoromethyl)phenyl406 methylanilino 4-chloro-2- 3-fluorophenyl 356 methylanilino4-chloro-2- 2,6-difluorophenyl 374 methylanilino 4-chloro-2-2-chlorophenyl 372 methylanilino 4-chloro-2- 3-(chloromethyl)phenyl 386methylanilino 4-chloro-2- 4-(2-(2- 394 methylanilinomethyl)propyl)phenyl 4-chloro-2- 3-chlorophenyl 372 methylanilino4-chloro-2- 2-nitrophenyl 383 methylanilino 4-chloro-2-3,5-dimethoxyphenyl 398 methylanilino 4-chloro-2- 2,6-dichlorophenyl 407methylanilino 4-chloro-2- 2,4-dichlorophenyl 407 methylanilino4-chloro-2- 4-fluorophenyl 356 methylanilino 4-chloro-2- 4-butylphenyl394 methylanilino 4-chloro-2- 2-methylphenyl 352 methylanilino4-chloro-2- phenyl 338 methylanilino 4-chloro-2- 4-ethylphenyl 366methylanilino 4-chloro-2- 2,3-difluorophenyl 374 methylanilino4-chloro-2- 2,6-dimethoxyphenyl 398 methylanilino 4-chloro-2-3,4-difluorophenyl 374 methylanilino 4-chloro-2- 2,5-difluorophenyl 374methylanilino 4-chloro-2- 4-ethoxyphenyl 382 methylanilino 4-chloro-2-2,4,6-trichlorophenyl 441 methylanilino 4-chloro-2- 3-methylphenyl 352methylanilino 4-chloro-2- 2-fluoro-5- 424 methylanilino(trifluoromethyl)phenyl 4-chloro-2- 3-methoxyphenyl 368 methylanilino4-chloro-2- thien-2-yl 344 methylanilino 4-chloro-2- 2-bromophenyl 417methylanilino 4-chloro-2- 4-bromophenyl 417 methylanilino 4-chloro-2-4-fluoro-3- 424 methylanilino (trifluoromethyl)phenyl 4-chloro-2-3-(trifluoromethoxy)phenyl 422 methylanilino 4-chloro-2-9-fluorenon-4-yl 440 methylanilino 4-chloro-2- isoxazol-5-yl 329methylanilino 4-chloro-2- benzofuroxan-5-yl 396 methylanilino4-chloro-2- 2-chloropyrid-3-yl 373 methylanilino 4-chloro-2-3,5-difluorophenyl 374 methylanilino 4-chloro-2- 2-(4- 445 methylanilinomethylphenoxy)pyridin-3-yl 4-chloro-2- pyridin-4-yl 339 methylanilino4-chloro-2- anthraquinon-2-yl 468 methylanilino 4-chloro-2- 2-iodophenyl464 methylanilino

The compounds listed in Table 7 can be prepared from substituted5-aminopyridine compounds and the appropriate acid chloride according tothe general procedure above.

TABLE 7 R¹X R³ 4-chloro-2-methylphenoxy 3,4-difluorphenyl4-chloro-2-methylphenoxy 4-pentylphenyl 4-chloro-2-methylphenoxy2-(4-chlorophenylthio) pyridin-3-yl 4-chloro-2-methylphenoxy2,6-dimethylphenyl 4-chloro-2-methylphenoxy 2,5-dimethoxyphenyl4-chloro-2-methylphenoxy 2,5-dichloropyridin-3-yl4-chloro-2-methylphenoxy 2-chloro-6-methoxypyridin- 4-yl4-chloro-2-methylphenoxy 2,3-dichloropyridin-5-yl4-chloro-2-methylphenoxy 1-naphthyl 4-chloro-2-methylphenoxy2,4-dimethoxyphenyl 4-chloro-2-methylphenoxy 3,5-bis(trifluoromethyl)phenyl 4-chloro-2-methylphenoxy 2-(4-chlorophenoxy)pyridin-3-yl 4-chloro-2-methylphenoxy pentafluorophenyl1-naphthoxy 4-pentylphenyl 1-naphthoxy 2-(4-chlorophenylthio)pyridin-3-yl 1-naphthoxy 2,6-dimethylphenyl 1-naphthoxy2,5-dimethoxyphenyl 1-naphthoxy 2,5-dichloropyridin-3-yl 1-naphthoxy2-chloro-6-methoxypyridin- 4-yl 1-naphthoxy 2,3-dichloropyridin-5-yl1-naphthoxy 1-naphthyl 1-naphthoxy 2,4-dimethoxyphenyl 1-naphthoxy3,5-bis(trifluoromethyl) phenyl 1-naphthoxy 2-(4-chlorophenoxy)pyridin-3-yl 1-naphthoxy pentafluorophenyl2-(2-propyl)phenoxy 4-pentylphenyl 2-(2-propyl)phenoxy2-(4-chlorophenylthio) pyridin-3-yl 2-(2-propyl)phenoxy2,6-dimethylphenyl 2-(2-propyl)phenoxy 2,5-dimethoxyphenyl2-(2-propyl)phenoxy 2,5-dichloropyridin-3-yl 2-(2-propyl)phenoxy2-chloro-6-methoxypyridin- 4-yl 2-(2-propyl)phenoxy2,3-dichloropyridin-5-yl 2-(2-propyl)phenoxy 1-naphthyl2-(2-propyl)phenoxy 2,4-dimethoxyphenyl 2-(2-propyl)phenoxy3,5-bis(trifluoromethyl) phenyl 2-(2-propyl)phenoxy 2-(4-chlorophenoxy)pyridin-3-yl 2-(2-propyl)phenoxy pentafluorophenyl3-fluoro-5-methylphenoxy 4-pentylphenyl 3-fluoro-5-methylphenoxy2-(4-chlorophenylthio) pyridin-3-yl 3-fluoro-5-methylphenoxy2,6-dimethylphenyl 3-fluoro-5-methylphenoxy 2,5-dimethoxyphenyl3-fluoro-5-methylphenoxy 2,5-dichloropyridin-3-yl3-fluoro-5-methylphenoxy 2-chloro-6-methoxypyridin- 4-yl3-fluoro-5-methylphenoxy 2,3-dichloropyridin-5-yl3-fluoro-5-methylphenoxy 1-naphthyl 3-fluoro-5-methylphenoxy2,4-dimethoxyphenyl 3-fluoro-5-methylphenoxy 3,5-bis(trifluoromethyl)phenyl 3-fluoro-5-methylphenoxy 2-(4- chlorophenoxy)pyridin-3-yl3-fluoro-5-methylphenoxy pentafluorophenyl 2-methylpyrid-3-yloxy4-pentylphenyl 2-methylpyrid-3-yloxy 2-(4-chlorophenylthio) pyridin-3-yl2-methylpyrid-3-yloxy 2,6-dimethylphenyl 2-methylpyrid-3-yloxy2,5-dimethoxyphenyl 2-methylpyrid-3-yloxy 2,5-dichloropyridin-3-yl2-methylpyrid-3-yloxy 2-chloro-6-methoxypyridin- 4-yl2-methylpyrid-3-yloxy 2,3-dichloropyridin-5-yl 2-methylpyrid-3-yloxy1-naphthyl 2-methylpyrid-3-yloxy 2,4-dimethoxyphenyl2-methylpyrid-3-yloxy 3,5-bis(trifluoromethyl) phenyl2-methylpyrid-3-yloxy 2-(4- chlorophenoxy)pyridin-3-yl2-methylpyrid-3-yloxy pentafluorophenyl 4-methoxyphenoxy 4-biphenyl4-methoxyphenoxy 4-cyanophenyl 4-methoxyphenoxy 3-cyanophenyl4-methoxyphenoxy 4-nitrophenyl 4-methoxyphenoxy 5-nitrofuran-2-yl4-methoxyphenoxy 3-nitrophenyl 4-methoxyphenoxy4-(trifluoromethyl)phenyl 4-methoxyphenoxy 2-nitrophenyl4-methoxyphenoxy thien-2-yl 2-(2-propoxy)phenoxy 4-biphenyl2-(2-propoxy)phenoxy 4-cyanophenyl 2-(2-propoxy)phenoxy 3-cyanophenyl2-(2-propoxy)phenoxy 4-nitrophenyl 2-(2-propoxy)phenoxy5-nitrofuran-2-yl 2-(2-propoxy)phenoxy 3-nitrophenyl2-(2-propoxy)phenoxy 2-nitrophenyl 2-(2-propoxy)phenoxy thien-2-yl2-(2-propoxy)phenoxy 3,5-difluorophenyl 4-fluorophenoxy 4-biphenyl4-fluorophenoxy 4-cyanophenyl 4-fluorophenoxy 3-cyanophenyl4-fluorophenoxy 4-nitrophenyl 4-fluorophenoxy 5-nitrofuran-2-yl4-fluorophenoxy 3-nitrophenyl 4-fluorophenoxy 2-nitrophenyl4-fluorophenoxy 4-(trifluoromethyl)phenyl 4-fluorophenoxy thien-2-yl4-fluorophenoxy 3,5-difluorophenyl 4-chlorophenoxy 4-biphenyl4-chlorophenoxy 4-cyanophenyl 4-chlorophenoxy 3-cyanophenyl4-chlorophenoxy 4-nitrophenyl 4-chlorophenoxy 5-nitrofuran-2-yl4-chlorophenoxy 3-nitrophenyl 4-chlorophenoxy 2-nitrophenyl4-chlorophenoxy 4-(trifluoromethyl)phenyl 4-chlorophenoxy thien-2-yl4-chlorophenoxy 3,5-difluorophenyl 2,4-difluorophenoxy 4-biphenyl2,4-difluorophenoxy 4-cyanophenyl 2,4-difluorophenoxy 3-cyanophenyl2,4-difluorophenoxy 4-nitrophenyl 2,4-difluorophenoxy 5-nitrofuran-2-yl2,4-difluorophenoxy 3-nitrophenyl 2,4-difluorophenoxy4-(trifluoromethyl)phenyl 2,4-difluorophenoxy 2-nitrophenyl4-chloro-2,5- 4-biphenyl dimethylphenoxy 4-chloro-2,5- 4-cyanophenyldimethylphenoxy 4-chloro-2,5- 3-cyanophenyl dimethylphenoxy4-chloro-2,5- 4-nitrophenyl dimethylphenoxy 4-chloro-2,5-5-nitrofuran-2-yl dimethylphenoxy 4-chloro-2,5- 3-nitrophenyldimethylphenoxy 4-chloro-2,5- 4-(trifluoromethyl)phenyl dimethylphenoxy4-chloro-2,5- 2-nitrophenyl dimethylphenoxy 4-chloro-2,5- thien-2-yldimethylphenoxy 4-chloro-2,5- 3,5-difluorophenyl dimethylphenoxy4-methoxyphenoxy 3,5-difluorophenyl 2-(2-propoxy)phenoxy4-(trifluoromethyl)phenyl 2,4-difluorophenoxy thien-2-yl2,4-difluorophenoxy 3,5-difluorophenyl 4-thiomethylphenoxy 4-biphenyl4-thiomethylphenoxy 4-cyanophenyl 4-thiomethylphenoxy 3-cyanophenyl4-thiomethylphenoxy 4-nitrophenyl 4-thiomethylphenoxy 5-nitrofuran-2-yl4-thiomethylphenoxy 3-nitrophenyl 4-thiomethylphenoxy4-(trifluoromethyl)phenyl 4-thiomethylphenoxy 2-nitrophenyl4-thiomethylphenoxy thien-2-yl 4-thiomethylphenoxy 3,5-difluorophenyl4-(2-(2-methyl)propyl) 4-biphenyl phenoxy 4-(2-(2-methyl)propyl)4-cyanophenyl phenoxy 4-(2-(2-methyl)propyl) 3-cyanophenyl phenoxy4-(2-(2-methyl)propyl) 4-nitrophenyl phenoxy 4-(2-(2-methyl)propyl)5-nitrofuran-2-yl phenoxy 4-(2-(2-methyl)propyl) 3-nitrophenyl phenoxy4-(2-(2-methyl)propyl) 4-(trifluoromethyl)phenyl phenoxy4-(2-(2-methyl)propyl) 2-nitrophenyl phenoxy 4-(2-(2-methyl)propyl)thien-2-yl phenoxy 4-(2-(2-methyl)propyl) 3,5-difluorophenyl phenoxy2,3-dimethylphenoxy 4-biphenyl 2,3-dimethylphenoxy 4-cyanophenyl2,3-dimethylphenoxy 3-cyanophenyl 2,3-dimethylphenoxy 4-nitrophenyl2,3-dimethylphenoxy 5-nitrofuran-2-yl 2,3-dimethylphenoxy 3-nitrophenyl2,3-dimethylphenoxy 4-(trifluoromethyl)phenyl 2,3-dimethylphenoxy2-nitrophenyl 2,3-dimethylphenoxy thien-2-yl 2,3-dimethylphenoxy3,5-difluorophenyl 3,5-(bis-2-propyl)phenoxy 4-biphenyl3,5-(bis-2-propyl)phenoxy 4-cyanophenyl 3,5-(bis-2-propyl)phenoxy3-cyanophenyl 3,5-(bis-2-propyl)phenoxy 4-nitrophenyl3,5-(bis-2-propyl)phenoxy 5-nitrofuran-2-yl 3,5-(bis-2-propyl)phenoxy3-nitrophenyl 3,5-(bis-2-propyl)phenoxy 4-(trifluoromethyl)phenyl3,5-(bis-2-propyl)phenoxy 2-nitrophenyl 3,5-(bis-2-propyl)phenoxythien-2-yl 3,5-(bis-2-propyl)phenoxy 3,5-difluorophenyl3-trifluoromethyl phenoxy 4-biphenyl 3-trifluoromethyl phenoxy4-cyanophenyl 3-trifluoromethyl phenoxy 3-cyanophenyl 3-trifluoromethylphenoxy 4-nitrophenyl 3-trifluoromethyl phenoxy 5-nitrofuran-2-yl3-trifluoromethyl phenoxy 3-nitrophenyl 3-trifluoromethyl phenoxy4-(trifluoromethyl)phenyl 3-trifluoromethyl phenoxy 2-nitrophenyl3-trifluoromethyl phenoxy thien-2-yl 3-trifluoromethyl phenoxy3,5-difluorophenyl 2,6-dichlorophenoxy 4-biphenyl 2,6-dichlorophenoxy4-cyanophenyl 2,6-dichlorophenoxy 3-cyanophenyl 2,6-dichlorophenoxy4-nitrophenyl 2,6-dichlorophenoxy 5-nitrofuran-2-yl 2,6-dichlorophenoxy3-nitrophenyl 2,6-dichlorophenoxy 4-(trifluoromethyl)phenyl2,6-dichlorophenoxy 2-nitrophenyl 2,6-dichlorophenoxy thien-2-yl2,6-dichlorophenoxy 3,5-difluorophenyl 2,4-dichlorophenoxy 4-biphenyl2,4-dichlorophenoxy 4-cyanophenyl 2,4-dichlorophenoxy 3-cyanophenyl2,4-dichlorophenoxy 4-nitrophenyl 2,4-dichlorophenoxy 5-nitrofuran-2-yl2,4-dichlorophenoxy 3-nitrophenyl 2,4-dichlorophenoxy4-(trifluoromethyl)phenyl 2,4-dichlorophenoxy 2-nitrophenyl2,4-dichlorophenoxy thien-2-yl 2,4-dichlorophenoxy 3,5-difluorophenyl4-chloro-3-methylphenoxy 4-biphenyl 4-chloro-3-methylphenoxy4-cyanophenyl 4-chloro-3-methylphenoxy 3-cyanophenyl4-chloro-3-methylphenoxy 4-nitrophenyl 4-chloro-3-methylphenoxy5-nitrofuran-2-yl 4-chloro-3-methylphenoxy 3-nitrophenyl4-chloro-3-methylphenoxy 2-nitrophenyl 4-chloro-3-methylphenoxythien-2-yl 4-chloro-3-methylphenoxy 3,5-difluorophenyl 4-chloro-2-4-biphenyl cyclohexylphenoxy 4-chloro-2- 4-cyanophenyl cyclohexylphenoxy4-chloro-2- 3-cyanophenyl cyclohexylphenoxy 4-chloro-2- 4-nitrophenylcyclohexylphenoxy 4-chloro-2- 5-nitrofuran-2-yl cyclohexylphenoxy4-chloro-2- 3-nitrophenyl cyclohexylphenoxy 4-chloro-2-4-(trifluoromethyl)phenyl cyclohexylphenoxy 4-chloro-2- 2-nitrophenylcyclohexylphenoxy 4-chloro-2- thien-2-yl cyclohexylphenoxy 4-chloro-2-3,5-difluorophenyl cyclohexylphenoxy 4-chloro-3,5- 4-biphenyldimethylphenoxy 4-chloro-3,5- 4-cyanophenyl dimethylphenoxy4-chloro-3,5- 3-cyanophenyl dimethylphenoxy 4-chloro-3,5- 4-nitrophenyldimethylphenoxy 4-chloro-3,5- 5-nitrofuran-2-yl dimethylphenoxy4-chloro-3,5- 3-nitrophenyl dimethylphenoxy 4-chloro-3,5-4-(trifluoromethyl)phenyl dimethylphenoxy 4-chloro-3,5- 2-nitrophenyldimethylphenoxy 4-chloro-3,5- thien-2-yl dimethylphenoxy 4-chloro-3,5-3,5-difluorophenyl dimethylphenoxy pyrid-3-yloxy 4-biphenylpyrid-3-yloxy 4-cyanophenyl pyrid-3-yloxy 3-cyanophenyl pyrid-3-yloxy4-nitrophenyl pyrid-3-yloxy 5-nitrofuran-2-yl pyrid-3-yloxy3-nitrophenyl pyrid-3-yloxy 4-(trifluoromethyl)phenyl pyrid-3-yloxy2-nitrophenyl pyrid-3-yloxy thien-2-yl pyrid-3-yloxy 3,5-difluorophenyl4-bromophenoxy 4-biphenyl 4-bromophenoxy 4-cyanophenyl 4-bromophenoxy3-cyanophenyl 4-bromophenoxy 4-nitrophenyl 4-bromophenoxy5-nitrofuran-2-yl 4-bromophenoxy 3-nitrophenyl 4-bromophenoxy4-(trifluoromethyl)phenyl 4-bromophenoxy 2-nitrophenyl 4-bromophenoxythien-2-yl 4-bromophenoxy 3,5-difluorophenyl 4-chloro-2- 4-pentylphenylmethylphenylthio 4-chloro-2- 2-(4-chlorophenylthio) methylphenylthiopyridin-3-yl 4-chloro-2- 2,6-dimethylphenyl methylphenylthio 4-chloro-2-2,5-dimethoxyphenyl methylphenylthio 4-chloro-2-2,5-dichloropyridin-3-yl methylphenylthio 4-chloro-2-2-chloro-6-methoxypyridin- methylphenylthio 4-yl 4-chloro-2-2,3-dichloropyridin-5-yl methylphenylthio 4-chloro-2- 1-naphthylmethylphenylthio 4-chloro-2- 2,4-dimethoxyphenyl methylphenylthio4-chloro-2- 3,5-bis(trifluoromethyl) methylphenylthio phenyl 4-chloro-2-2-(4- methylphenylthio chlorophenoxy)pyridin-3-yl 4-chloro-2-pentafluorophenyl methylphenylthio 4-chloro-2-methylanilino4-pentylphenyl 4-chloro-2-methylanilino 2-(4-chlorophenylthio)pyridin-3-yl 4-chloro-2-methylanilino 2,6-dimethylphenyl4-chloro-2-methylanilino 2,5-dimethoxyphenyl 4-chloro-2-methylanilino2,5-dichloropyridin-3-yl 4-chloro-2-methylanilino2-chloro-6-methoxypyridin- 4-yl 4-chloro-2-methylanilino2,3-dichloropyridin-5-yl 4-chloro-2-methylanilino 1-naphthyl4-chloro-2-methylanilino 2,4-dimethoxyphenyl 4-chloro-2-methylanilino3,5- bis(trifluoromethyl)phenyl 4-chloro-2-methylanilino 2-(4-chlorophenoxy)pyridin-3-yl 4-chloro-2-methylanilino pentafluorophenyl

EXAMPLE 19

General procedure for the synthesis of6-(substituted-amino)-N-substituted nicotinamides

Step A. General procedure for the preparation of 6-chloro-N-substitutednicotinamide:

To a suspension of 6-chloronicotinoyl chloride (1.76 g, 10.0 mmol) indry dichloromethane (10 mL) was added the amine (R³R⁴NH) (10.0 mmol)followed by the dropwise addition of triethylamine (1.7 mL, 12.2 mmol).After stirring for 40 min. at room temperature, the mixture was dilutedwith dichloromethane, washed with aqueous 1 M hydrochloric acid,saturated aqueous sodium hydrogencarbonate and water, dried over sodiumsulfate and concentrated to dryness under reduce pressure to afford thedesired nicotinamide.

The following compounds were prepared according to this procedure usingthe appropriate substituted amine:

6-Chloro-N-o-tolylnicotinamide: MS (m/z): 247/249 (M+H)⁺; C₁₃H₁₁ClN₂O₁requires 246.5.

6-Chloro-N-(2-fluorophenyl)nicotinamide: MS (m/z): 251/253 (M+H)⁺;C₁₂H₈Cl₁F₁N₂O₁ requires 250.7.

6-Chloro-N-(2,6-dimethylphenyl)nicotinamide: MS (m/z): 261/263 (M+H)⁺;C₁₄H₁₃Cl₁N₂O₁ requires 260.7.

6-Chloro-N-(2-phenoxyphenyl)nicotinamide: MS (m/z): 325/327 (M+H)⁺;C₁₈H₁₃ClN₂O₁ requires 324.8.

6-Chloro-N-phenylnicotinamide: MS (m/z): 233/235 (M+H)⁺; C₁₂H₈ClN₂O₁requires 232.7.

6-Chloro-N-(2,4-difluorophenyl)nicotinamide: MS (m/z): 269/271 (M+H)⁺;C₁₂H₇Cl₁F₂N₂O₁ requires 2:68.6.

6-Chloro-N-(2,6-diisopropylphenyl)nicotinamide: MS (m/z): 317/319(M+H)⁺; C₁₈H₂₁Cl₁N₂O₁ requires 316.8.

6-Chloro-N-(4-chlorophenyl)-N-methylnicotinamide: MS (m/z): 281/283(M+H)⁺; C₁₃H₁₀Cl₂N₂O₁ requires 281.1.

6-Chloro-N-(2,4-dimethoxyphenyl)nicotinamide: MS (m/z): 293/295 (M+H)⁺;C₁₄H₁₃Cl₁N₂O₃ requires 292.7.

6-Chloro-N-(3-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H)⁺;C₁₃H₁₁Cl₁N₂O₂ requires 262.7.

6-Chloro-N-(4-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H)⁺;C₁₃H₁₁Cl₁N₂O₂ requires 262.7.

6-Chloro-N-(2-methoxyphenyl)nicotinamide: MS (m/z): 263/265 (M+H)⁺;C₁₃H₁₁Cl₁N₂O₂ requires 262.7.

6-Chloro-N-methyl-N-phenylnicotinamide: MS (m/z): 247/249 (M+H)⁺;C₁₃H₁₁Cl₁N₂O₁ requires 246.7.

N-Benzyl-6-chloronicotinamide: MS (m/z): 247/249 (M+H)⁺; C₁₃H₁₁Cl₁N₂O₁requires 246.7.

Step B. General procedure for the preparation of6-(substituted-amino)-N-substituted nicotinamides

A mixture of the 6-chloro-N-substituted nicotinamide (12.5 mmol) andamine (R¹NH₂ or R¹NHCH₃) (20 mmol) in ethylene glycol (50 mL) orpyridine (alkylamines) (50 mL) was heated to 140° C. for 20 hours. Aftercooling to room temperature, the mixture was diluted withdichloromethane/methanol (9:1, 250 mL) and filtered through a plug ofsilica gel, washing with additional dichloromethane/methanol (9:1, 250mL). Concentration under reduced pressure afforded the desired6-(substituted-amino)-N-substituted nicotinamide.

The compounds listed in Tables 8-11 were prepared from6-chloro-N-substituted nicotinamides compounds and the appropriate amineaccording to the general procedure above.

TABLE 8

MS R³ R¹ (m/z) o-tolyl phenyl 303 o-tolyl o-tolyl 317 o-tolyl4-chloro-2-methylphenyl 352 o-tolyl 2-fluorophenyl 321 o-tolyl3-fluorophenyl 321 o-tolyl 4-fluorophenyl 321 o-tolyl 2,4-difluorophenyl339 o-tolyl 2-methoxyphenyl 333 o-tolyl 3-methoxyphenyl 333 o-tolyl4-methoxyphenyl 333 o-tolyl 2,4-dimethoxyphenyl 363 o-tolyl2-phenoxyphenyl 395 o-tolyl 3-phenoxyphenyl 395 o-tolyl 4-phenoxyphenyl395 o-tolyl 4-biphenyl 379 o-tolyl 4-benzylphenyl 393 o-tolyl4-(trifluoromethoxy)phenyl 387 o-tolyl cyclohexyl 309 o-tolyl2-methylcyclohexyl 323 o-tolyl cycloheptyl 323 o-tolyl indan-1-yl 343o-tolyl 2-dicyclohexyl 492 2-fluorophenyl phenyl 307 2-fluorophenylo-tolyl 321 2-fluorophenyl 4-chloro-2-methylphenyl 356 2-fluorophenyl2-fluorophenyl 325 2-fluorophenyl 3-fluorophenyl 325 2-fluorophenyl4-fluorophenyl 325 2-fluorophenyl 2,4-difluorophenyl 343 2-fluorophenyl2-methoxyphenyl 337 2-fluorophenyl 3-methoxyphenyl 337 2-fluorophenyl4-methoxyphenyl 337 2-fluorophenyl 2,4-dimethoxyphenyl 3672-fluorophenyl 2-phenoxyphenyl 399 2-fluorophenyl 3-phenoxyphenyl 3992-fluorophenyl 4-phenoxyphenyl 399 2-fluorophenyl 4-biphenyl 3832-fluorophenyl 4-benzylphenyl 397 2-fluorophenyl4-(trifluoromethoxy)phenyl 391 2-fluorophenyl cyclohexyl 3132-fluorophenyl 2-methylcyclohexyl 327 2-fluorophenyl cycloheptyl 3272-fluorophenyl indan-1-yl 347 2-fluorophenyl 2-dicyclohexyl 3952,6-dimethylphenyl phenyl 317 2,6-dimethylphenyl o-tolyl 3312,6-dimethylphenyl 4-chloro-2-methylphenyl 366 2,6-dimethylphenyl2-fluorophenyl 335 2,6-dimethylphenyl 3-fluorophenyl 3352,6-dimethylphenyl 4-fluorophenyl 335 2,6-dimethylphenyl2,4-difluorophenyl 353 2,6-dimethylphenyl 2-methoxyphenyl 3472,6-dimethylphenyl 3-methoxyphenyl 347 2,6-dimethylphenyl4-methoxyphenyl 347 2,6-dimethylphenyl 2,4-dimethoxyphenyl 3772,6-dimethylphenyl 2-phenoxyphenyl 409 2,6-dimethylphenyl3-phenoxyphenyl 409 2,6-dimethylphenyl 4-phenoxyphenyl 4092,6-dimethylphenyl 4-biphenyl 393 2,6-dimethylphenyl 4-benzylphenyl 4072,6-dimethylphenyl 4-(trifluoromethoxy)phenyl 401 2,6-dimethylphenylcyclohexyl 323 2,6-dimethylphenyl 2-methylcyclohexyl 3372,6-dimethylphenyl cycloheptyl 667 2,6-dimethylphenyl indan-1-yl 3572,6-dimethylphenyl 2-dicyclohexyl 406 2-phenoxyphenyl phenyl 3812-phenoxyphenyl o-tolyl 395 2-phenoxyphenyl 4-chloro-2-methylphenyl 4302-phenoxyphenyl 2-fluorophenyl 399 2-phenoxyphenyl 3-fluorophenyl 3992-phenoxyphenyl 4-fluorophenyl 399 2-phenoxyphenyl 2,4-difluorophenyl417 2-phenoxyphenyl 2-methoxyphenyl 411 2-phenoxyphenyl 3-methoxyphenyl411 2-phenoxyphenyl 4-methoxyphenyl 411 2-phenoxyphenyl2,4-dimethoxyphenyl 441 2-phenoxyphenyl 2-phenoxyphenyl 4732-phenoxyphenyl 3-phenoxyphenyl 473 2-phenoxyphenyl 4-phenoxyphenyl 4732-phenoxyphenyl 4-biphenyl 457 2-phenoxyphenyl 4-benzylphenyl 4722-phenoxyphenyl 4-(trifluoromethoxy)phenyl 465 2-phenoxyphenylcyclohexyl 387 2-phenoxyphenyl 2-methylcyclohexyl 401 2-phenoxyphenylcycloheptyl 401 2-phenoxyphenyl indan-1-yl 421 2-phenoxyphenyl2-cyclohexyl 470 phenyl phenyl 289 phenyl o-tolyl 303 phenyl4-chloro-2-methylphenyl 338 phenyl 2-fluorophenyl 307 phenyl3-fluorophenyl 307 phenyl 4-fluorophenyl 307 phenyl 2,4-difluorophenyl325 phenyl 2-methoxyphenyl 319 phenyl 3-methoxyphenyl 319 phenyl4-methoxyphenyl 319 phenyl 2,4-dimethoxyphenyl 349 phenyl2-phenoxyphenyl 381 phenyl 3-phenoxyphenyl 381 phenyl 4-phenoxyphenyl381 phenyl 4-biphenyl 365 phenyl 4-benzylphenyl 379 phenyl4-(trifluoromethoxy)phenyl 373 phenyl cyclohexyl 295 phenyl2-methylcyclohexyl 309 phenyl cycloheptyl 309 phenyl indan-1-yl 329phenyl 2-dicyclohexyl 377 2,4-difluorophenyl phenyl 3252,4-difluorophenyl o-tolyl 339 2,4-difluorophenyl4-chloro-2-methylphenyl 374 2,4-difluorophenyl 2-fluorophenyl 3432,4-difluorophenyl 3-fluorophenyl 343 2,4-difluorophenyl 4-fluorophenyl343 2,4-difluorophenyl 2,4-difluorophenyl 361 2,4-difluorophenyl2-methoxyphenyl 355 2,4-difluorophenyl 3-methoxyphenyl 3552,4-difluorophenyl 4-methoxyphenyl 355 2,4-difluorophenyl2,4-dimethoxyphenyl 385 2,4-difluorophenyl 2-phenoxyphenyl 4172,4-difluorophenyl 3-phenoxyphenyl 417 2,4-difluorophenyl4-phenoxyphenyl 417 2,4-difluorophenyl 4-biphenyl 401 2,4-difluorophenyl4-benzylphenyl 415 2,4-difluorophenyl 4-(trifluoromethoxy)phenyl 4092,4-difluorophenyl cyclohexyl 331 2,4-difluorophenyl 2-methylcyclohexyl345 2,4-difluorophenyl cycloheptyl 345 2,4-difluorophenyl indan-1-yl 3652,4-difluorophenyl 2-dicyclohexyl 413 2,6-diisopropylphenyl phenyl 3732,6-diisopropylphenyl o-tolyl 387 2,6-diisopropylphenyl4-chloro-2-methylphenyl 422 2,6-diisopropylphenyl 2-fluorophenyl 3912,6-diisopropylphenyl 3-fluorophenyl 391 2,6-diisopropylphenyl4-fluorophenyl 391 2,6-diisopropylphenyl 2,4-difluorophenyl 4092,6-diisopropylphenyl 2-methoxyphenyl 403 2,6-diisopropylphenyl3-methoxyphenyl 403 2,6-diisopropylphenyl 4-methoxyphenyl 4032,6-diisopropylphenyl 2,4-dimethoxyphenyl 434 2,6-diisopropylphenyl2-phenoxyphenyl 466 2,6-diisopropylphenyl 3-phenoxyphenyl 4662,6-diisopropylphenyl 4-phenoxyphenyl 466 2,6-diisopropylphenyl4-biphenyl 450 2,6-diisopropylphenyl 4-benzylphenyl 4642,6-diisopropylphenyl 4-(trifluoromethoxy)phenyl 4572,6-diisopropylphenyl cyclohexyl 380 2,6-diisopropylphenyl2-methylcyclohexyl 394 2,6-diisopropylphenyl cycloheptyl 3942,6-diisopropylphenyl indan-1-yl 414 2,6-diisopropylphenyl2-dicyclohexyl 462 2,4-dimethoxyphenyl phenyl 349 2,4-dimethoxyphenylo-tolyl 363 2,4-dimethoxyphenyl 4-chloro-2-methylphenyl 3982,4-dimethoxyphenyl 2-fluorophenyl 367 2,4-dimethoxyphenyl3-fluorophenyl 367 2,4-dimethoxyphenyl 4-fluorophenyl 3672,4-dimethoxyphenyl 2,4-difluorophenyl 385 2,4-dimethoxyphenyl2-methoxyphenyl 379 2,4-dimethoxyphenyl 3-methoxyphenyl 3792,4-dimethoxyphenyl 4-methoxyphenyl 379 2,4-dimethoxyphenyl2,4-dimethoxyphenyl 409 2,4-dimethoxyphenyl 2-phenoxyphenyl 4412,4-dimethoxyphenyl 3-phenoxyphenyl 441 2,4-dimethoxyphenyl4-phenoxyphenyl 441 2,4-dimethoxyphenyl 4-biphenyl 4252,4-dimethoxyphenyl 4-benzylphenyl 439 2,4-dimethoxyphenyl4-(trifluoromethoxy)phenyl 433 2,4-dimethoxyphenyl3-trifluoromethylphenyl 417 2,4-dimethoxyphenyl cyclohexyl 3552,4-dimethoxyphenyl 2-methylcyclohexyl 369 3-methoxyphenyl phenyl 3193-methoxyphenyl o-tolyl 333 3-methoxyphenyl 4-chloro-2-methylphenyl 3683-methoxyphenyl 2-fluorophenyl 337 3-methoxyphenyl 3-fluorophenyl 3373-methoxyphenyl 4-fluorophenyl 337 3-methoxyphenyl 2,4-difluorophenyl355 3-methoxyphenyl 2-methoxyphenyl 349 3-methoxyphenyl 3-methoxyphenyl349 3-methoxyphenyl 4-methoxyphenyl 349 3-methoxyphenyl2,4-dimethoxyphenyl 379 3-methoxyphenyl 2-phenoxyphenyl 4113-methoxyphenyl 3-phenoxyphenyl 411 3-methoxyphenyl 4-phenoxyphenyl 4113-methoxyphenyl 4-biphenyl 395 3-methoxyphenyl 4-benzylphenyl 4093-methoxyphenyl 4-(trifluoromethoxy)phenyl 403 3-methoxyphenyl3-trifluoromethylphenyl 387 3-methoxyphenyl cyclohexyl 6253-methoxyphenyl 2-methylcyclohexyl 339 4-methoxyphenyl phenyl 3194-methoxyphenyl o-tolyl 333 4-methoxyphenyl 4-chloro-2-methylphenyl 3684-methoxyphenyl 2-fluorophenyl 337 4-methoxyphenyl 3-fluorophenyl 3374-methoxyphenyl 4-fluorophenyl 337 4-methoxyphenyl 2,4-difluorophenyl355 4-methoxyphenyl 2-methoxyphenyl 349 4-methoxyphenyl 3-methoxyphenyl349 4-methoxyphenyl 4-methoxyphenyl 349 4-methoxyphenyl2,4-dimethoxyphenyl 379 4-methoxyphenyl 2-phenoxyphenyl 4114-methoxyphenyl 3-phenoxyphenyl 411 4-methoxyphenyl 4-phenoxyphenyl 4114-methoxyphenyl 4-biphenyl 395 4-methoxyphenyl 4-benzylphenyl 4094-methoxyphenyl 4-(trifluoromethoxy)phenyl 403 4-methoxyphenyl3-trifluoromethylphenyl 387 4-methoxyphenyl cyclohexyl 6254-methoxyphenyl 2-methylcyclohexyl 339 2-methoxyphenyl phenyl 3192-methoxyphenyl o-tolyl 333 2-methoxyphenyl 4-chloro-2-methylphenyl 3682-methoxyphenyl 2-fluorophenyl 337 2-methoxyphenyl 3-fluorophenyl 3372-methoxyphenyl 4-fluorophenyl 337 2-methoxyphenyl 2,4-difluorophenyl355 2-methoxyphenyl 2-methoxyphenyl 349 2-methoxyphenyl 3-methoxyphenyl349 2-methoxyphenyl 4-methoxyphenyl 349 2-methoxyphenyl2,4-dimethoxyphenyl 379 2-methoxyphenyl 2-phenoxyphenyl 4112-methoxyphenyl 3-phenoxyphenyl 411 2-methoxyphenyl 4-phenoxyphenyl 4112-methoxyphenyl 4-biphenyl 395 2-methoxyphenyl 4-benzylphenyl 4092-methoxyphenyl 4-(trifluoromethoxy)phenyl 403 2-methoxyphenyl3-trifluoromethylphenyl 387 2-methoxyphenyl cyclohexyl 6252-methoxyphenyl 2 -methylcyclohexyl 339

TABLE 9

MS R³ R¹ (m/z) 4-chlorophenyl phenyl 338 4-chlorophenyl o-tolyl 3524-chlorophenyl 4-chloro-2-methylphenyl 386 4-chlorophenyl 2-fluorophenyl356 4-chlorophenyl 3-fluorophenyl 356 4-chlorophenyl 4-fluorophenyl 3564-chlorophenyl 2,4-difluorophenyl 374 4-chlorophenyl 2-methoxyphenyl 3684-chlorophenyl 3-methoxyphenyl 368 4-chlorophenyl 4-methoxyphenyl 3684-chlorophenyl 2,4-dimethoxyphenyl 398 4-chlorophenyl 2-phenoxyphenyl430 4-chlorophenyl 3-phenoxyphenyl 430 4-chlorophenyl 4-phenoxyphenyl430 4-chlorophenyl 4-biphenyl 414 4-chlorophenyl 4-benzylphenyl 4284-chlorophenyl 4-(trifluoromethoxy)phenyl 422 4-chlorophenyl cyclohexyl344 4-chlorophenyl 2-methylcyclohexyl 358 phenyl phenyl 303 phenylo-tolyl 317 phenyl 4-chloro-2-methylphenyl 352 phenyl 2-fluorophenyl 321phenyl 3-fluorophenyl 321 phenyl 4-fluorophenyl 321 phenyl2,4-difluorophenyl 339 phenyl 2-methoxyphenyl 333 phenyl 3-methoxyphenyl333 phenyl 4-methoxyphenyl 333 phenyl 2,4-dimethoxyphenyl 363 phenyl2-phenoxyphenyl 395 phenyl 3-phenoxyphenyl 395 phenyl 4-phenoxyphenyl395 phenyl 4-biphenyl 379 phenyl 4-benzylphenyl 393 phenyl4-(trifluoromethoxy)phenyl 387 phenyl 3-trifluoromethylphenyl 371 phenylcyclohexyl 309 phenyl 2-methylcyclohexyl 323

TABLE 10

MS R³ R¹ (m/z) o-tolyl N-methylphenyl 317 o-tolyl4-chloro-N-methylphenyl 352 o-tolyl N-methylcyclohexyl 3232-fluorophenyl N-methylphenyl 321 2-fluorophenyl 4-chloro-N-methylphenyl356 2-fluorophenyl N-methylcyclohexyl 327 2,6-dimethylphenylN-methylphenyl 331 2,6-dimethylphenyl 4-chloro-N-methylphenyl 3662,6-dimethylphenyl N-methylcyclohexyl 337 2-phenoxyphenyl N-methylphenyl395 2-phenoxyphenyl 4-chloro-N-methylphenyl 430 2-phenoxyphenylN-methylcyclohexyl 401 phenyl N-methylphenyl 303 phenyl4-chloro-N-methylphenyl 338 phenyl N-methylcyclohexyl 3092,4-difluorophenyl N-methylphenyl 339 2,4-difluorophenyl4-chloro-N-methylphenyl 374 2,4-difluorophenyl N-methylcyclohexyl 3452,6-diisopropylphenyl N-methylphenyl 387 2,6-diisopropylphenyl4-chloro-N-methylphenyl 422 2,6-diisopropylphenyl N-methylcyclohexyl 3942,4-dimethoxyphenyl N-methylphenyl 363 2,4-dimethoxyphenyl4-chloro-N-methylphenyl 398 2,4-dimethoxyphenyl N-methylcyclohexyl 3693-methoxyphenyl N-methylphenyl 333 3-methoxyphenyl4-chloro-N-methylphenyl 368 3-methoxyphenyl N-methylcyclohexyl 3394-methoxyphenyl N-methylphenyl 333 4-methoxyphenyl4-chloro-N-methylphenyl 368 4-methoxyphenyl N-methylcyclohexyl 3392-methoxyphenyl N-methylphenyl 333 2-methoxyphenyl4-chloro-N-methylphenyl 368 2-methoxyphenyl N-methylcyclohexyl 339

TABLE 11

MS R³ R¹ (m/z) 4-chlorophenyl phenyl 352 4-chlorophenyl 4-chlorophenyl386 4-chlorophenyl cyclohexyl 358 phenyl phenyl 317 phenyl4-chlorophenyl 352 phenyl cyclohexyl 323

The compounds listed in Tables 12-13 can be prepared from6-chloro-N-substituted nicotinamides compounds and the appropriate amineaccording to the general procedure above.

TABLE 12

R¹X R³ o-tolyl 3-trifluoromethylphenyl 2-fluorophenyl3-trifluoromethylphenyl 2,6-dimethylphenyl 3-trifluoromethylphenyl2-phenoxyphenyl 3-trifluoromethylphenyl phenyl 3-trifluoromethylphenyl2,4-difluorophenyl 3-trifluoromethylphenyl 2,6-diisopropylphenyl3-trifluoromethylphenyl 2,4-dimethoxyphenyl cycloheptyl2,4-dimethoxyphenyl indan-1-yl 2,4-dimethoxyphenyl 2-dicyclohexyl3-methoxyphenyl cycloheptyl 3-methoxyphenyl indan-1-yl 3-methoxyphenyl2-dicyclohexyl 4-methoxyphenyl cyclohexyl 4-methoxyphenyl indan-1-yl4-methoxyphenyl 2-dicyclohexyl 2-methoxyphenyl cycloheptyl2-methoxyphenyl indan-1-yl 2-methoxyphenyl 2-dicyclohexyl

TABLE 13

R¹X R³ 4-chlorophenyl 3-trifluoromethylphenyl 4-chlorophenyl cycloheptyl4-chlorophenyl indan-1-yl 4-chlorophenyl 2-dicyclohexyl phenylcycloheptyl phenyl indan-1-yl phenyl 2-dicyclohexyl

EXAMPLE 20

The following assays were used to characterize the ability of compoundsof the invention to inhibit the production of TNF-α and IL-1-β. Thesecond assay measured the inhibition of TNF-α and/or IL-1-β in miceafter oral administration of the test compounds. The third assay, aglucagon binding inhibition in vitro assay, can be used to characterizethe ability of compounds of the invention to inhibit glucagon binding.The fourth assay, a Cyclooxygenase enzyme (COX-1 and COX-2) inhibitionactivity in vitro assay, can be used to characterize the ability ofcompounds of the invention to inhibit COX-1 and/or COX-2. The fifthassay, a Raf-kinase inhibition assay, can be used to characterize thecompounds of the invention to inhibit phosphorylation of MEK byactivated Raf-kinase.

Lipopolysaccharide-activated monocyte TNF production assay

Isolation of monocytes

Test compounds were evaluated in vitro for the ability to inhibit theproduction of tumor necrosis factor (TNF) by monocytes activated withbacterial lipopolysaccharide (LPS). Fresh residual source leukocytes (abyproduct of plateletpheresis) were obtained from a local blood bank,and peripheral blood mononuclear cells (PBMCs) were isolated by densitygradient centrifugation on Ficol-Paque Plus (Pharmacia). PBMCs weresuspended at 2×10⁶/ml in DMEM supplemented to contain 2% FCS, 10 mM, 0.3mg/ml glutamate, 100 U/ml penicillin G and 100 mg/ml streptomycinsulfate (complete media). Cells were plated into Falcon flat bottom, 96well culture plates (200 μl/well) and cultured overnight at 37° C. and6% CO₂. Non-adherent cells were removed by washing with 200 μl/well offresh medium. Wells containing adherent cells (˜70% monocytes) werereplenished with 100 μl of fresh medium.

Preparation of test compound stock solutions

Test compounds were dissolved in DMSO. Compound stock solutions wereprepared to an initial concentration of 10-50 μM. Stocks were dilutedinitially to 20-200 μM in complete media. Nine two-fold serial dilutionsof each compound were then prepared in complete medium.

Treatment of cells with test compounds and activation of TNF productionwith lipopolysaccharide

One hundred microliters of each test compound dilution were added tomicrotiter wells containing adherent monocytes and 100 μl completemedium. Monocytes were cultured with test compounds for 60 min at whichtime 25 μl of complete medium containing 30 ng/ml lipopolysaccharidefrom E. coli K532 were added to each well. Cells were cultured anadditional 4 hrs. Culture supernatants were then removed and TNFpresence in the supernatants was quantified using an ELISA.

TNF ELISA

Flat bottom, 96 well Corning High Binding ELISA plates were coatedovernight (4° C.) with 150 μL/well of 3 μg/ml murine anti-human TNF-αMAb (R&D Systems #MAB210). Wells were then blocked for 1 hr at roomtemperature with 200 μL/well of CaCl₂-free ELISA buffer supplemented tocontain 20 mg/ml BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mMCaCl₂, 0.15 mM thimerosal, pH 7.4). Plates were washed and replenishedwith 100 μl of test supernatants (diluted 1:3) or standards. Standardsconsisted of eleven 1.5-fold serial dilutions from a stock of 1 ng/mlrecombinant human TNF (R&D Systems). Plates were incubated at roomtemperature for 1 hr on orbital shaker (300 rpm), washed and replenishedwith 100 μl/well of 0.5 μg/ml goat anti-human TNF-α (R&D systems#AB-210-NA) biotinylated at a 4:1 ratio. Plates were incubated for 40min, washed and replenished with 100 μl/well of alkalinephosphatase-conjugated streptavidin (Jackson ImmunoResearch#016-050-084) at 0.02 μg/ml. Plates were incubated 30 min, washed andreplenished with 200 μl/well of 1 mg/ml of p-nitrophenyl phosphate.After 30 min, plates were read at 405 nm on a V_(max) plate reader.

Data analysis

Standard curve data were fit to a second order polynomial and unknownTNF-α concentrations determined from their OD by solving this equationfor concentration. TNF concentrations were then plotted vs. testcompound concentration using a second order polynomial. This equationwas then used to calculate the concentration of test compounds causing a50% reduction in TNF production.

The following compounds had an IC₅₀ of less than 15 μM:

2-cyclohexyloxy-5-(2-chlorophenylcarbonylamino)pyridine;

2-cyclohexyloxy-5-(2-methylphenylcarbonylamino)pyridine;

2-cyclohexyloxy-5-(2,6-dichlorophenylcarbonylamino) pyridine;

2-cyclohexyloxy-5-(2,6-dimethylphenylcarbonylamino) pyridine;

2-(2,4-dimethylphenoxy)-5-(2-methylphenylcarbonylamino) pyridine;

2-(2-methyl-4-fluorophenoxy)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-(2-chlorophenylcarbonyl amino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-(2,6-dichlorophenylcarbonylamino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-(2,6-dimethylphenylcarbonylamino)pyridine;

2-(4-chlorophenoxy)-5-(2,6-dimethylphenylcarbonylamino) pyridine;

2-(2-methyl-4-fluorophenoxy)-5-(2,6-dichlorophenylcarbonylamino)pyridine;

2-(2-methyl-4-fluorophenoxy)-5-(2,6-dimethylphenylcarbonylamino)pyridine;

2-(2-methyl-4-fluorophenoxy)-5-(2-fluorophenylcarbonyl amino)pyridine;

2-(2,4-dimethylphenoxy)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;

2-(l-naphthyloxy)-5-(2-methylphenylcarbonylamino) pyridine;

2-(1-naphthyloxy)-5-(2,6-dichlorophenylcarbonylamino) pyridine;

2-(2-methyl-3-pyridyloxy)-5-(2,6-dichlorophenylcarbonyl amino)pyridine;

2-(2-methyl-4-chlorophenoxy)-5-((3,5-dimethyl-4-isoxazolyl)carbonylamino)pyridine;

2-cyclohexylamino-5-(2,6-dichlorophenylcarbonylamino) pyridine;

2-cyclohexylamino-5-(2,6-dimethylphenylcarbonylamino) pyridine;

2-(2-methylcyclohexylamino)-5-(2,6-dichlorophenylcarbonylamino)pyridine;

2-(2-methylcyclohexylamino)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2-methylphenylamino)-5-(2-methylphenylcarbonyl amino)pyridine;

2-(2-methylphenylamino)-5-(2,6-dimethylphenylcarbonyl amino)pyridine;

2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenylcarbonylamino)pyridine; and

2-(2-methyl-4-chlorophenylamino)-5-(2-methylphenylaminocarbonyl)pyridine.

Compounds of the invention can also be shown to inhibit LPS-inducedrelease of IL-1β, IL-6 and/or IL-8 from monocytes by measuringconcentrations of IL-1β, IL-6 and/or IL-8 by methods well known to thoseskilled in the art. In a similar manner to the above described assayinvolving the LPS induced release of TNF-α from monocytes, compounds ofthis invention can also be shown to inhibit LPS induced release ofIL-1β, IL-6 and/or IL-8 from monocytes by measuring concentrations ofIL-1β, IL-6 and/or IL-8 by methods well known to those skilled in theart. Thus, the compounds of the invention may lower elevated levels ofTNF-α, IL-1, IL-6, and IL-8 levels. Reducing elevated levels of theseinflammatory cytokines to basal levels or below is favorable incontrolling, slowing progression, and alleviating many disease states.All of the compounds are useful in the methods of treating diseasestates in which TNF-A, IL-1β, IL-6, and IL-8 play a role to the fullextent of the definition of TNF-α-mediated diseases described herein.

Inhibition of LPS-Induced TNF-α production in mice

Male DBA/1LACJ mice are dosed with vehicle or test compounds in avehicle (the vehicle consisting of 0.5% tragacanth in 0.03 N HCl) 30minutes prior to lipopolysaccharide (2 mg/kg, I.V.) injection. Ninetyminutes after LPS injection, blood are collected and the serum isanalyzed by ELISA for TNF levels.

Selected compounds from the class have shown in vivo activity in a LPSmouse model in which serum levels of TNF-α were reduced in the presenceof compounds of this invention.

Compounds of the invention may be shown to have anti-inflammatoryproperties in animal models of inflammation, including carageenan pawedema, collagen induced arthritis and adjuvant arthritis, such as thecarageenan paw edema model (C. A. Winter et al Proc. Soc. Exp. Biol.Med. (1962) vol 111, p 544; K. F. Swingle, in R. A. Scherrer and M. W.Whitehouse, Eds., Antiinflammatory Agents, Chemistry and Pharmacology,Vol. 13-II, Academic, New York, 1974, p. 33) and collagen inducedarthritis (D. E. Trentham et al J. Exp. Med. (1977) vol. 146, p 857; J.S. Courtenay, Nature (New Biol.) (1980), Vol 283, p 666).

¹²⁵I-Glucagon Binding Screen with CHO/hGLUR Cells

The assay is described in WO 97/16442, which is incorporated herein byreference in its entirety.

Reagents

The reagents can be prepared as follows: (a) prepare fresh 1Mo-Phenanthroline (Aldrich) (198.2 mg/ml ethanol); (b) prepare fresh 0.5MDTT (Sigma); (c) Protease Inhibitor Mix (1000×): 5 mg leupeptin, 10 mgbenzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per mlDMSO and store aliquots at −20° C.; (d) 250 μm human glucagon(Peninsula): solubilize 0.5 mg vial in 575 μl 0.1N acetic acid (1 μlyields 1 μM final concentration in assay for non-specific binding) andstore in aliquots at −20° C.; (e) Assay Buffer: 20 mM Tris (pH 7.8), 1mM DTT and 3 mM o-phenanthroline; (f) Assay Buffer with 0.1% BSA (fordilution of label only; 0.01% final in assay): 10 μl 10% BSA(heat-inactivated) and 990 μl Assay Buffer; (g) ¹²⁵I-Glucagon (NEN,receptor-grade, 2200 Ci/mmol): dilute to 50,000 cpm/25 μl in assaybuffer with BSA (about 50 pM final concentration in assay).

Harvesting of CHO/hGLUR Cells for Assay

1. Remove media from confluent flask then rinse once each with PBS (Ca,Mg-free) and Enzyme-free Dissociation Fluid (Specialty Media, Inc.).

2. Add 10 ml Enzyme-free Dissoc. Fluid and hold for about 4 min. at 37°C.

3. Gently tap cells free, triturate, take aliquot for counting andcentrifuge remainder for 5 min. at 1000 rpm.

4. Resuspend pellet in Assay Buffer at 75000 cells per 100 μl.

Membrane preparations of CHO/hGLUR cells can be used in place of wholecells at the same assay volume. Final protein concentration of amembrane preparation is determined on a per batch basis.

Assay

The determination of inhibition of glucagon binding can be carried outby measuring the reduction of I¹²⁵-glucagon binding in the presence ofcompounds of Formula I. The reagents are combined in 120 μL of assaybuffer as follows:

Compound/ 250 μM ¹²⁵I- CHO/hGLUR Vehicle Glucagon Glucagon Cells Total—/5 μl — 25 μl 100 μl Binding + 5 μl/— — 25 μl 100 μl CompoundNonspecific —/5 μl 1 μl 25 μl 100 μl Binding

The mixture is incubated for 60 min. at 22° C. on a shaker at 275 rpm.The mixture is filtered over pre-soaked (0.5% polyethylimine (PEI)) GF/Cfiltermat using an Innotech Harvester or Tomtec Harvester with fourwashes of ice-cold 20 mM Tris buffer (pH 7.8). The radioactivity in thefilters is determined by a gamma-scintillation counter.

Thus, compounds of the invention may also be shown to inhibit thebinding of glucagon to glucagon receptors.

Cyclooxygenase Enzyme Activity Assay

The human monocytic leukemia cell line, THP-1, differentiated byexposure to phorbol esters expresses only COX-1; the human osteosarcomacell line 143B expresses predominantly COX-2. THP-1 cells are routinelycultured in RPMI complete media supplemented with 10% FBS and humanosteosarcoma cells (HOSC) are cultured in minimal essential mediasupplemented with 10% fetal bovine serum (MEM-10%FBS); all cellincubations are at 37° C. in a humidified environment containing 5% CO₂.

COX-1 Assay

In preparation for the COX-1 assay, THP-1 cells are grown to confluency,split 1:3 into RPMI containing 2% FBS and 10 mM phorbol 12-myristate13-acetate (TPA), and incubated for 48 hours on a shaker to preventattachment. Cells are pelleted and resuspended in Hank's Buffered Saline(HBS) at a concentration of 2.5×10⁶ cells/mL and plated in 96-wellculture plates at a density of 5×10⁵ cells/mL. Test compounds arediluted in HBS and added to the desired final concentration and thecells are incubated for an additional 4 hours. Arachidonic acid is addedto a final concentration of 30 mM, the cells incubated for 20 minutes at37° C., and enzyme activity determined as described below.

COX-2 Assay

For the COX-2 assay, subconfluent HOSC are trypsinized and resuspendedat 3×10⁶ cells/mL in MEM-FBS containing 1 ng human IL-1b/mL, plated in96-well tissue culture plates at a density of 3×10⁴ cells per well,incubated on a shaker for 1 hour to evenly distribute cells, followed byan additional 2 hour static incubation to allow attachment. The media isthen replaced with MEM containing 2% FBS (MEM-2%FBS) and 1 ng humanIL-1b/mL, and the cells incubated for 18-22 hours. Following replacementof media with 190 mL MEM, 10 mL of test compound diluted in HBS is addedto achieve the desired concentration and the cells incubated for 4hours. The supernatants are removed and replaced with MEM containing 30mM arachidonic acid, the cells incubated for 20 minutes at 37° C., andenzyme activity determined as described below.

COX Activity Determined

After incubation with arachidonic acid, the reactions are stopped by theaddition of 1 N HCl, followed by neutralization with 1 N NaOH andcentrifugation to pellet cell debris. Cyclooxygenase enzyme activity inboth HOSC and THP-1 cell supernatants is determined by measuring theconcentration of PGE₂ using a commercially available ELISA (Neogen#404110). A standard curve of PGE₂ is used for calibration, andcommercially available COX-1 and COX-2 inhibitors are included asstandard controls.

The following compound exhibits activities in the Cyclooxygenase assaywith IC₅₀ values of 10 μM or less:2-(2,4-dimethylphenylamino)-5-(2,6-dichlorophenylcarbonylamino)pyridine.

Raf Kinase assay

In vitro Raf kinase activity is measured by the extent ofphosphorylation of the substrate MEK (Map kinase/ERK kinase) byactivated Raf kinase. Phosphorylated MEK is trapped on a filter andincorporation of radiolabeled phosphate is quantified by scintillationcounting.

MATERIALS:

Activated Raf is produced by triple transfection of Sf9 cells withbaculoviruses expressing “Glu-Glu”-epitope tagged Raf,val¹²-H-Ras, andLck. The “Glu-Glu”-epitope, Glu-Try-Met-Pro-Met-Glu, was fused to thecarboxy-terminus of full length c-Raf.

Catalytically inactive MEK (K97A mutation) is produced in Sf9 cellstransfected with a baculovirus expressing c-terminus “Glu-Glu”epitope-tagged K97A MEK1.

Anti “Glu-Glu” antibody was purified from cells grown as described in:Grussenmeyer, et al., Proceedings of the National Academy of Science,U.S.A. pp 7952-7954, 1985.

Column buffer: 20 mM Tris pH=8, 100 mM NaCl, 1 mM EDTA, 2.5 mM EGTA, 10mM MgCl₂, 2 mM DTT, 0.4 mM AEBSF, 0.1% n-octylglucopyranoside, 1 nMokadeic acid, and 10 μg/mL each of benzamidine, leupeptin, pepstatin,and aprotinin.

5× Reaction buffer: 125 mM HEPES pH=:8, 25 mM MgCl₂, 5 mM EDTA, 5 mMNa₃VO₄, 100 μg/mL BSA.

Enzyme dilution buffer: 25 mM HEPES pH=8, 1 mM EDTA, 1 mM Na₃VO₄, 400μg/mL BSA.

Stop solution: 100 mM EDTA, 80 mM sodium pyrophosphate.

Filter plates: Milipore multiscreen # SE3MO78E3, Immobilon-P (PVDF).

METHODS:

Protein purification: Sf9 cells were infected with baculovirus and grownas described in Williams, et al., Proceedings of the National Academy ofScience, U.S.A. pp 2922-2926, 1992. All subsequent steps were preformedon ice or at 4° C. Cells were pelleted and lysed by sonication in columnbuffer. Lysates were spun at 17,000×g for 20 min, followed by 0.22 μMfiltration. Epitope tagged proteins were purified by chromatography overGammaBind Plus affinity column to which the “Glu-Glu” antibody wascoupled. Proteins were loaded on the column followed by sequentialwashes with two column volumes of column buffer, and eluted with 50μg/mL Glu-Tyr-Met-Pro-Met-Glu in column buffer.

Raf kinase assay: Test compounds were evaluated using ten 3-fold serialdilutions starting at 10-100 μM. 10 μL of the test inhibitor or control,dissolved in 10% DMSO, was added to the assay plate followed by theaddition of 30 μL of the a mixture containing 10 μL 5× reaction buffer,1 mM ³³P-γ-ATP (20 μCi/mL), 0.5 μL MEK (2.5 mg/mL), 1 μL 50 mMβ-mercaptoethanol. The reaction was started by the addition of 10 μL ofenzyme dilution buffer containing 1 mM DTT and an amount of activatedRaf that produces linear kinetics over the reaction time course. Thereaction was mixed and incubated at room temperature for 90 min. andstopped by the addition of 50 μL stop solution. 90 μL aliquots of thisstopped solution were transferred onto GFP-30 cellulose microtiterfilter plates (Polyfiltronics), the filter plates washed in four wellvolumes of 5% phosphoric acid, allowed to dry, and then replenished with25 μl scintillation cocktail. The plates were counted for ³³P gammaemission using a TopCount Scintillation Reader.

Accordingly, the compounds of the invention or a pharmaceuticalcomposition thereof are useful for prophylaxis and treatment ofrheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma;uveititis; acute and chronic myelogenous leukemia; pancreatic β celldestruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis;inflammatory bowel disease; adult respiratory distress syndrome (ARDS);psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis;anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexiel;Reiter's syndrome; type I and type II diabetes; bone resorptiondiseases; graft vs. host reaction; ischemia reperfusion injury;atherosclerosis; brain trauma; Alzheimer's disease; stroke; myocardialinfarction; multiple sclerosis; cerebral malaria; sepsis; septic shock;toxic shock syndrome; fever, and myalgias due to infection. HIV-1,HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpesviruses (including HSV-1, HSV-2), and herpes zoster, all of which aresensitive to TNF-α and/or IL-1 inhibition or glucagon antagonism, willalso be positively effected by the compounds and methods of theinvention.

The compounds of the present invention may also possess oncolyticcharacteristics and may be useful for the treatment of cancer. Thecompounds of the present invention may also block signal transduction byextracellular mitogenic stimuli and oncoproteins through inhibition ofRaf kinase.

The compounds of the present invention also may possess analgesicproperties and may be useful for the treatment of pain disorders, suchas hyperalgesia due to excessive IL-1. The compounds of the presentinvention may also prevent the production of prostaglandins byinhibition of enzymes in the human arachidonic acid/prostaglandinpathway, including cyclooxygenase (WO 96/03387, incorporated herein byreference in its entirety).

Because of their ability to lower TNF-α and IL-1 concentrations orinhibit glucagon binding to its receptor, the compounds of the inventionare also useful research tools for studying the physiology associatedwith blocking these effects.

The methods of the invention comprise administering an effective dose ofa compound of the invention, a pharmaceutical salt thereof, or apharmaceutical composition of either, to a subject i.e., an animal,preferably a mammal, most preferably a human) in need of a reduction inthe level of TNF-α, IL-1, IL-6, and/or IL-8 levels and/or reduction inplasma glucose levels and/or which subject may be suffering fromrheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma;uveititis; acute and chronic myelogenous leukemia; pancreatic β celldestruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis;inflammatory bowel disease; adult respiratory distress syndrome (ARDS);psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis;anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia;Reiter's syndrome; type I and type II diabetes; cancer; bone resorptiondiseases; graft vs. host reaction; Alzheimer's disease; stroke;myocardial infarction; ischemia reperfusion injury; atherosclerosis;brain trauma; multiple sclerosis; cerebral malaria; sepsis; septicshock; toxic shock syndrome; fever, and myalgias due to infection, orwhich subject is infected by HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV),influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), orherpes zoster.

In another aspect, this invention comprises the use of a compound of theinvention, or pharmaceutically acceptable salts thereof, in themanufacture of a medicament for the treatment either acutely orchronically of a TNF-α, IL-1β, IL-6, and/or IL-8 mediated disease state,including those described previously. The compounds of the present arealso useful in the manufacture of an anti-cancer medicant. The compoundsof the present invention are also useful in the manufacture of amedicant to attenuate or prevent signal transduction by extracellularmitogenic stimuli and oncoproteins through inhibition of Raf kinase.Also, the compounds of this invention are useful in the manufacture of aanalgesic medicament and a medicament for treating pain disorders, suchas hyperalgesia. The compounds of the present invention also are usefulin the manufacture of a medicament to prevent the production ofprostaglandins by inhibition of enzymes in the human arachidonicacid/prostaglandin pathway.

In still another aspect, this invention provides a pharmaceuticalcomposition comprising an effective TNF-α, IL-1β, IL-6, and/or IL-8lowering amount and/or effective plasma glucose level lowering amount,and/or effective tumor supressing amount of a compound of the inventionand a pharmaceutically acceptable carrier or diluent, and if desiredother active ingredients. The compounds of the invention areadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds of the present invention required to arrest the progressor prevent tissue damage associated with the disease are readilyascertained by one of ordinary skill in the art using standard methods.

For the treatment of TNF-α, IL-1β, IL-6, and IL-8 mediated diseases,cancer, and/or hyperglycemia, the compounds of the present invention maybe administered orally, parentally, by inhalation spray, rectally, ortopically in dosage unit formulations containing conventionalpharmaceutically acceptable carriers, adjuvants, and vehicles. The termparenteral as used herein includes, subcutaneous, intravenous,intramuscular, intrasternal, infusion techniques or intraperitoneally.

The dosage regimen for treating a TNF-α, IL-1, IL-6, and IL-8 mediateddiseases, cancer, and/or hyperglycemia with the compounds of thisinvention and/or compositions of this invention is based on a variety offactors, including the type of disease, the age, weight, sex, medicalcondition of the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or Liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulphuric acids, acacia, gelatin, sodium alginate,polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hyroxy-ethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein X is O, S, S(O),S(O)₂ or NR²; Y is —C(O)—NR³R⁴ or —NR⁴—C(O)—R³; R¹ is a cycloalkyl oraryl radical which is optionally substituted by 1-4 radicals of alkyl,halo, haloalkyl, cyano, azido, nitro, amidino, R¹⁸—Z^(—) orR¹⁸—Z¹⁸-alkyl; provided that the total number of aryl, heteroaryl,cycloalkyl and heterocyclyl radicals in R¹ is 1-3; and provided when Yis —NR⁴—C(O)— R² is a hydrogen or alkyl radical; R³ is a heteroarylradical which is optionally substituted by 1-5 radicals of alkyl, halo,haloalkyl, cyano, azido, nitro, amidino, R¹⁹—Z¹⁹— or R¹⁹—Z¹⁹-alkyl;provided that the total number of aryl and heteroaryl radicals in R³ is1-3; R⁴ is a hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl or R²⁰—Z²⁰-alkyl radical; whereinneither R³ or R⁴ is 3-(2,6-dihalophenyl)-5-methylisoxazol-4yl or5-methoxy-6-trifluoromethylindol-1-yl; wherein R¹⁸, R¹⁹ and R²⁰ are eachindependently a hydrogen, alkyl, haloalkyl, aryl, heteroalkyl, arylalkylor heteroarylalkyl radical; wherein the aryl and heteroaryl radicals ofR⁴, R¹⁸, R¹⁹ and R²⁰ are optionally substituted by 1-3 radicals ofhydroxy, alkoxy, alkylthiol, amino, alkylamino, dialkylamino,alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl,alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl,haloalkyl or haloalkoxy; and Z¹⁸, Z¹⁹ and Z²⁰ are each independently—O—, —S—, —S(O)—, —S(O)₂—, —CO₂—, —C(O)—, —NR²¹—, —NR²¹—C(O)—,—C(O)—NR²¹—, —NR²¹—S(O)₂— or —S(O)₂—NR²¹—; wherein each R²¹ isindependently a hydrogen or alkyl radical; R⁵ and R⁶ are eachindependently a hydrogen, alkyl, halo, haloalkyl, haloalkoxy,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amino, alkylamino,dialkylamino, alkanoylamino, alkylsulfonylamino, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy, hydroxyalkyl, thiol,alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy, alkoxyalkyl, cyano,azido, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonylor dialkylaminocarbonyl radical; and R⁷ is a hydrogen, alkyl, halo,haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, hydroxy,hydroxyalkyl, thiol, alkylthiol, alkylsulfinyl, alkylsulfonyl, alkoxy,alkoxyalkyl, cyano, azido, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl radical. 2.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R¹ is a cycloalkyl or aryl radical which is optionallysubstituted by 1-4 radicals of C₁-C₆ alkyl, halo, C₁-C₆ haloalkyl of 1-3halo radicals, cyano, azido, nitro, amidino, R¹⁸—Z¹⁸— or R¹⁸—Z¹⁸—C₁-C₆alkyl; provided that the total number of aryl, heteroaryl, cycloalkyland heterocyclyl radicals in R¹ is 1-3; R² is a hydrogen or C₁-C₄ alkylradical; R³ is a heteroaryl radical which is optionally substituted by1-5 radicals of C₁-C₆ alkyl, halo, C₁-C₆ haloalkyl of 1-3 halo radicals,cyano, azido, nitro, amidino, R¹⁹—Z¹⁹— or R¹⁹—Z¹⁹—C₁-C₆ alkyl; providedthat the total number of aryl and heteroaryl radicals in R³ is 1-3; R⁴is a radical of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl of1-3 halo radicals, C₂-C₆ haloalkenyl of 1-3 halo radicals, aryl,heteroaryl, aryl-C₁-C₄ alkyl, heteroaryl-C₁-C₄ alkyl or R²⁰—Z²⁰—C₁-C₆alkyl radical; wherein neither R³ or R⁴ is3-(2,6-dihalophenyl)-5-methylisoxazol-4yl or5-methoxy-6-trifluoromethylindol-1-yl; and wherein R¹⁸, R¹⁹ and R²⁰ areeach independently a hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 haloradicals, aryl, heteroaryl, aryl-C₁-C₄ alkyl or heteroaryl-C₁-C₄ alkylradical; wherein the aryl and heteroaryl radicals of R⁴, R¹⁸, R¹⁹ andR²⁰ are optionally substituted by 1-3 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, C₁-c₅alkanoylamino, C₁-C₄ alkylsulfonylamino, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, (C₁-C₄ alkoxy)carbonylamino, (C₁-C₄ alkoxy)carbonyl,cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals orC₁-C₄ haloalkoxy of 1-3 halo radicals; and each R²¹ is independently ahydrogen or C₁-C₄ alkyl radical; R⁵ and R⁶ are each independently ahydrogen, C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl of 1-3 halo radicals, C₁-C₄haloalkoxy of 1-3 halo radicals, C₁-C₄ aminoalkyl,(C₁-C₄alkyl)amino-C₁-C₄ alkyl, di(C₁-C₄ alkyl)amino-C₁-C₄ alkyl, amino,C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, C₁-C₄alkylsulfonylamino, aminosulfonyl, C₁-C₄ alkylaminosulfonyl, di(C₁-C₄alkyl)aminosulfonyl, hydroxy, C₁-C₄ hydroxyalkyl, thiol, C₁-C₄alkylthiol, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxy,(C₁-C₄ alkoxy)C₁-C₄ alkyl, cyano, azido, nitro, carboxy, (C₁-C₄alkoxy)carbonyl, aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl or di(C₁-C₄alkyl)aminocarbonyl radical; and R⁷ is a hydrogen, C₁-C₄ alkyl, halo,C₁-C₄ haloalkyl of 1-3 halo radicals, C₁-C₄ haloalkoxy of 1-3 haloradicals, C₁-C₄ aminoalkyl, (C₁-C₄ alkyl)amino-C₁-C₄ alkyl, di(C₁-C₄alkyl)amino-C₁-C₄ alkyl, aminosulfonyl, C₁-C₄ alkylaminosulfonyl,di(C₁-C₄ alkyl)aminosulfonyl, hydroxy, C₁-C₄ hydroxyalkyl, thiol, C₁-C₄alkylthiol, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxy,(C₁-C₄ alkoxy)C₁-C₄ alkyl, cyano, azido, nitro, carboxy, (C₁-C₄alkoxy)carbonyl, aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl or di(C₁-C₄alkyl)aminocarbonyl radical; and wherein cycloalkyl is a monocyclic,bicyclic or tricyclic carbocyclic alkyl radical of 5-12 ring members,which is optionally partially unsaturated, benzo fused or heterocyclofused; aryl is a phenyl or biphenyl radical which is optionally benzofused or heterocyclo fused; heterocyclyl is a radical of a monocyclic orbicyclic saturated heterocyclic ring system having 5-8 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally partially unsaturated or benzo-fusedand optionally substituted by 1-2 oxo or thioxo radicals; and heteroarylis a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6ring members per ring, wherein 1-3 ring members are oxygen, sulfur ornitrogen heteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-carbocyclic-fused.
 3. The compound of claim 2 or apharmaceutically acceptable salt thereof, wherein Y is —NR⁴—C(O)—R³. 4.The compound of claim 3 or a pharmaceutically acceptable salt thereof,wherein X is O or NR²; R¹ is a cycloalkyl or aryl radical which isoptionally substituted by 1-4 radicals of C₁-C₄ alkyl, halo, C₁-C₄haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R¹⁸—Z¹⁸—or R¹⁸—Z¹⁸—C₁-C₄ alkyl; provided that the total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R¹ is 1-2; whereineach R¹⁸ is independently a hydrogen, C₁-C₄ alkyl, trifluoromethyl,aryl, heteroaryl, aryl-C₁-C₂ alkyl or heteroaryl-C₁-C₂ alkyl radical;wherein the aryl and heteroaryl radicals are optionally substituted by1-2 radicals of hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol, amino, C₁-C₄alkylamino, di(C₁-C₄ alkyl)amino, acetylamino, cyano, halo, azido, C₁-C₄alkyl, trifluoromethyl or trifluoromethoxy; and R² is a hydrogen orC₁-C₂ alkyl radical; R³ is an aryl or heteroaryl radical which isoptionally substituted by 1-5 radicals of C₁-C₆ alkyl, halo, C₁-C₄haloalkyl of 1-3 halo radicals, cyano, azido, nitro, amidino, R¹⁹—Z¹⁹—or R¹⁹—Z¹⁹—C₁-C₄ alkyl; provided that the total number of aryl andheteroaryl radicals in R³ is 1-2; and wherein each R¹⁹ is independentlya hydrogen, C₁-C₄ alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₄alkyl or heteroaryl-C₁-C₄ alkyl radical; wherein the aryl and heteroarylradicals are optionally substituted by 1-2 radicals of hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino,acetylamino, cyano, halo, C₁-C₄ alkyl, trifluoromethyl ortrifluoromethoxy; and R⁴ is a radical of hydrogen, C₁-C₆ alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl, heteroaryl-C₁-C₄ alkyl or R²⁰—Z²⁰—C₂-C₄alkyl radical; wherein neither R³ or R⁴ is3-(2,6-dihalophenyl)-5-methylisoxazol-4-yl or5-methoxy-6-trifluoromethylindol-1-yl; and wherein R²⁰ is a hydrogen,C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₂ alkyl or heteroaryl-C₁-C₂alkyl radical; wherein the aryl and heteroaryl radicals of R⁴ and R²⁰are optionally substituted by 1-2 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino,acetylamino, halo, C₁-C₄ alkyl, trifluoromethyl or trifluoromethoxy; andZ²⁰ is —O— or —NR²¹—; wherein each R²¹ is independently a hydrogen ormethyl radical; R⁵ and R⁶ are each independently a hydrogen, C₁-C₄alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C₁-C₄ alkylamino,di(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, hydroxy, C₁-C₄ hydroxyalkyl,C₁-C₄ alkoxy, cyano, azido, nitro, carboxy, (C₁-C₄ alkoxy)carbonyl,aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl or di(C₁-C4alkyl)aminocarbonylradical; and R⁷ is a hydrogen, C₁-C₄ alkyl, halo, trifluoromethyl,trifluoromethoxy, hydroxy, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, carboxy,(C₁-C₄ alkoxy)carbonyl, aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl ordi(C₁-C₄ alkyl)aminocarbonyl radical; and wherein cycloalkyl is amonocyclic or bicyclic carbocyclic alkyl radical of 5-12 ring members,which is optionally partially unsaturated, benzo fused or heterocyclofused; aryl is a phenyl or biphenyl radical which is optionally benzofused or heterocyclo fused; heterocyclyl is a radical of a monocyclic orbicyclic saturated heterocyclic ring system having 5-8 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally partially unsaturated or benzo-fusedand optionally substituted by 1-2 oxo or thioxo radicals; and heteroarylis a monocyclic aromatic heterocyclic ring system having 5-6 ringmembers per ring, wherein 1-3 ring members are oxygen, sulfur ornitrogen heteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-carbocyclic-fused.
 5. The compound of claim 4 or apharmaceutically acceptable salt thereof, wherein R³is a radical of theformula

wherein U is C—R¹³ or N; V and W are each independently C—R¹² or N;wherein at least one of U, V and W is N; R¹¹ and R¹³ are eachindependently a radical of hydrogen, C₁-C₄ alkyl, halo, trifluoromethyl,cyano, azido, nitro, amidino or R¹⁹—Z¹⁹—; and each R¹² is independentlya radical of hydrogen, C₁-C₆ alkyl, halo, C₁-C₄ haloalkyl of 1-3 haloradicals, R³¹—Z³¹— or R³¹—Z³¹—C₁-C₄ alkyl; provided that the combinedtotal number of aryl and heteroaryl radicals in R¹¹, R¹² and R¹³ is 0-1;wherein each R¹⁹ is independently a hydrogen, C₁-C₄ alkyl,trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl or heteroaryl-C₁-C₄alkyl radical; wherein the aryl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino,methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl,trifluoromethyl or trifluoromethoxy; and each Z¹⁹ is independently —O—,—S(O)₂—, —CO₂—, —C(O)—, —NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or—S(O)₂—NR²¹—; wherein each R³¹ is independently a hydrogen, C₁-C₄ alkyl,trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl or heteroaryl-C₁-C₄alkyl radical; wherein the aryl and heteroaryl radicals are optionallysubstituted by 1-2 radicals of hydroxy, methoxy, ethoxy, amino,methylamino, dimethylamino, acetylamino, cyano, halo, methyl, ethyl,trifluoromethyl or trifluoromethoxy; and each Z³¹ is independently —O—,—NR²¹—, —NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or —S(O)₂—NR²¹—; whereinR⁴ is a radical of hydrogen, C₁-C₆ alkyl, aryl, heteroaryl, aryl-C₁-C₄alkyl, heteroaryl-C₁-C₄ alkyl or R²⁰—Z²⁰—C₂-C₄ alkyl radical; whereinR²⁰ is a hydrogen, C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₂ alkyl orheteroaryl-C₁-C₂ alkyl radical; wherein the aryl and heteroaryl radicalsof R⁴ and R²⁰ are optionally substituted by 1-2 radicals of hydroxy,methoxy, ethoxy, methylthiol, ethylthiol, amino, methylamino,dimethylamino, ethylamino, diethylamino, acetylamino, halo, methyl,ethyl, trifluoromethyl or trifluoromethoxy; and R⁵ and R⁶ are eachindependently a hydrogen, methyl, ethyl, halo, trifluoromethyl,trifluoromethoxy, amino, C₁-C₂ alkylamino, di(C₁-C₂ alkyl)amino,hydroxy, methoxy or ethoxy radical; and R⁷ is a hydrogen, methyl, ethyl,halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxy or ethoxyradical; and wherein cycloalkyl is a monocyclic or bicyclic carbocyclicalkyl radical of 5-10 ring members, which is optionally partiallyunsaturated with one double bond, benzo fused or heterocyclo fused; arylis a phenyl or biphenyl radical which is optionally benzo fused orheterocyclo fused; heterocyclyl is a radical of a monocyclic or bicyclicsaturated heterocyclic ring system having 5-8 ring members per ring,wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms,which is optionally partially unsaturated or benzo-fused and optionallysubstituted by 1-2 oxo or thioxo radicals; and heteroaryl is amonocyclic aromatic heterocyclic ring system having 5-6 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-carbocyclic-fused.
 6. The compound of claim 5 or apharmaceutically acceptable salt thereof, wherein R¹ is a radical of theformula

wherein R²², R²³, R²⁴, R²⁵ and R²⁶ are each independently a radical ofhydrogen, C₁-C₄ alkyl, halo, trifluoromethyl, cyano, azido, nitro,amidino, R¹⁸—Z¹⁸— or R¹⁸—Z¹⁸—C₁-C₄ alkyl; provided at least one of R²¹,R²², R²³, R²⁴ and R²⁵ is hydrogen; and provided that the combined totalnumber of aryl and heteroaryl radicals in R²², R²³, R²⁴, R²⁵ and R²⁶ is0-1; wherein each Z¹⁸ is independently —O—, —S—, —S(O)₂—, —CO₂—, —NR²¹—,—NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or —S(O)₂—NR²¹—; and wherein arylis a phenyl or biphenyl radical which is optionally benzo fused orheterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclicring system having 5-6 ring members per ring, wherein 1-3 ring membersare oxygen, sulfur or nitrogen heteroatoms, which is optionallybenzo-fused or saturated C₃-C₄-carbocyclic-fused.
 7. The compound ofclaim 6 or a pharmaceutically acceptable salt thereof, wherein X is NR²;R² is a hydrogen or methyl radical; R⁴ is a radical of hydrogen, methylor ethyl radical; and R⁵, R⁶ and R⁷ are each independently a hydrogenradical; and wherein aryl is a phenyl, biphenyl or naphthyl radical; andheteroaryl is a monocyclic aromatic heterocyclic ring system having 5-6ring members per ring, wherein 1-3 ring members are oxygen, sulfur ornitrogen heteroatoms.
 8. The compound of claim 7 or a pharmaceuticallyacceptable salt thereof, wherein R¹¹ and R¹³ are each independently aradical of hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl,cyano, azido, nitro, amidino, R¹⁹—O—, R¹⁹—S(O)₂—, R¹⁹—O—C(O)—,R¹⁹—C(O)—, R¹⁹—NR¹²—C(O)— or R¹⁹—NR²¹—S(O)₂—; and each R¹² isindependently a radical of hydrogen, methyl, ethyl, fluoro, chloro,trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, amino, methylamino,dimethylamino, acetylamino, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, aminomethyl, (methylamino)methyl or(dimethylamino)methyl; provided that the combined total number of aryland heteroaryl radicals in R¹¹, R¹² and R¹³ is 0-1; and wherein each R¹⁹is independently a hydrogen, methyl, ethyl, trifluoromethyl, phenyl,heteroaryl, phenylmethyl or heteroaryl-methyl radical; wherein thephenyl and heteroaryl radicals are optionally substituted by 1-2radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino,acetylamino, cyano, fluoro, chloro, methyl, ethyl, trifluoromethyl ortrifluoromethoxy.
 9. The compound of claim 2 or a pharmaceuticallyacceptable salt thereof, wherein Y is —C(O)—NR³R⁴.
 10. The compound ofclaim 9 or a pharmaceutically acceptable salt thereof, wherein X is O orNR²; R¹ is a cycloalkyl or aryl radical which is optionally substitutedby 1-4 radicals of C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl of 1-3 haloradicals, cyano, azido, nitro, amidino, R¹⁸—Z¹⁸— or R¹⁸—Z¹⁸—C₁-C₄ alkyl;provided that the total number of aryl, heteroaryl, cycloalkyl andheterocyclyl radicals in R¹ is 1-2; wherein each R¹⁸ is independently ahydrogen, C₁-C₄ alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₂alkyl or heteroaryl-C₁-C₂ alkyl radical; wherein the aryl and heteroarylradicals are optionally substituted by 1-2 radicals of hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino,acetylamino, cyano, halo, azido, C₁-C₄ alkyl, trifluoromethyl ortrifluoromethoxy; and each Z¹⁸ is independently —O—, —S—, —S(O)—,—S(O)₂—, —CO₂—, —C(O)—, —NR²¹—, —NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂—or —S(O)₂—NR²¹—; wherein each R²¹ is independently a hydrogen or C₁-C₄alkyl radical; R² is a hydrogen or C₁-C₂ alkyl radical; R³ is aheteroaryl radical which is optionally substituted by 1-5 radicals ofC₁-C₆ alkyl, halo, C₁-C₄ haloalkyl of 1-3 halo radicals, cyano, azido,nitro, amidino, R¹⁹—Z¹⁹— or R¹⁹—Z¹⁹—C₁-C₄ alkyl; provided that the totalnumber of aryl and heteroaryl radicals in R³ is 1-2; wherein each R¹⁹ isindependently a hydrogen, C₁-C₄ alkyl, trifluoromethyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl or heteroaryl-C₁-C₄ alkyl radical; whereinthe aryl and heteroaryl radicals are optionally substituted by 1-2radicals of hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol, amino, C₁-C₄alkylamino, di(C₁-C₄ alkyl)amino, acetylamino, cyano, halo, C₁-C₄ alkyl,trifluoromethyl or trifluoromethoxy; and R⁴ is a radical of hydrogen,C₁-C₆ alkyl, aryl, heteroaryl, aryl-C1-C₄ alkyl, heteroaryl-C1-C₄ alkylor R²⁰—Z²⁰—C₂-C₄ alkyl radical; wherein neither R³ or R⁴ is3-(2,6-dihalophenyl)-5-methylisoxazol-4-yl or5-methoxy-6-trifluoromethylindol-1-yl; and wherein R²⁰ is a hydrogen,C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₂ alkyl or heteroaryl-C₁-C₂alkyl radical; wherein the aryl and heteroaryl radicals of R⁴ and R²⁰are optionally substituted by 1-2 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino,acetylamino, halo, C₁-C₄ alkyl, trifluoromethyl or trifluoromethoxy; andZ²⁰ is —O— or —NR²¹—; wherein each R²¹ is independently a hydrogen ormethyl radical; R⁵ and R⁶ are each independently a hydrogen, C₁-C₄alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, C₁-C₄ alkylamino,di(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, hydroxy, C₁-C₄ hydroxyalkyl,C₁-C₄ alkoxy, cyano, azido, nitro, carboxy, (C₁-C₄ alkoxy)carbonyl,aminocarbonyl, (C₁-C₄ alkyl)aminocarbonyl or di(C₁-C₄alkyl)aminocarbonyl radical; and R⁷ is a hydrogen, C₁-C₄ alkyl, halo,trifluoromethyl, trifluoromethoxy, hydroxy, C₁-C₄ hydroxyalkyl, C₁-C₄alkoxy, carboxy, (C₁-C₄ alkoxy)carbonyl, aminocarbonyl, (C₁-C₄alkyl)aminocarbonyl or di(C₁-C₄ alkyl)aminocarbonyl radical; and whereincycloalkyl is a monocyclic or bicyclic carbocyclic alkyl radical of 5-12ring members, which is optionally partially unsaturated, benzo fused orheterocyclo fused; aryl is a phenyl or biphenyl radical which isoptionally benzo fused or heterocyclo fused; heterocyclyl is a radicalof a monocyclic or bicyclic saturated heterocyclic ring system having5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfuror nitrogen heteroatoms, which is optionally partially unsaturated orbenzo-fused and optionally substituted by 1-2 oxo or thioxo radicals;and heteroaryl is a monocyclic aromatic heterocyclic ring system having5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfuror nitrogen heteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-carbocyclic-fused.
 11. The compound of claim 10 or apharmaceutically acceptable salt thereof, wherein R³ is a radical of theformula

wherein U is C—R¹³ or N; V and W are each independently C—R¹² or N; R¹¹and R¹³ are each independently a radical of hydrogen, C₁-C₄ alkyl, halo,trifluoromethyl, cyano, azido, nitro, amidino or R¹⁹—Z¹⁹—; and each R¹²is independently a radical of hydrogen, C₁-C₆ alkyl, halo, C₁-C₄haloalkyl of 1-3 halo radicals, R³¹—Z³¹— or R³¹—Z³¹—C₁-C₄ alkyl;provided that the combined total number of aryl and heteroaryl radicalsin R¹¹, R¹² and R¹³ is 0-1; provided when U is C—R¹³ and V and W areeach C—R¹², R¹¹ and R¹³ are each other than a nitro, cyano, carboxy oralkoxycarbonyl radical; wherein each R¹⁹ is independently a hydrogen,C₁-C₄ alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl orheteroaryl-C₁-C₄ alkyl radical; wherein the aryl and heteroaryl radicalsare optionally substituted by 1-2 radicals of hydroxy, methoxy, ethoxy,amino, methylamino, dimethylamino, acetylamino, cyano, halo, methyl,ethyl, trifluoromethyl or trifluoromethoxy; and each Z¹⁹ isindependently —O—, —S(O)₂—, —CO₂—, —C(O)—, —NR²¹—C(O)—, —C(O)—NR²¹—,—NR²¹—S(O)₂— or —S(O)₂—NR²¹—; wherein each R²¹ is independently ahydrogen or methyl radical; wherein each R³¹ is independently ahydrogen, C₁-C₄ alkyl, trifluoromethyl, aryl, heteroaryl, aryl-C₁-C₄alkyl or heteroaryl-C₁-C₄ alkyl radical; wherein the aryl and heteroarylradicals are optionally substituted by 1-2 radicals of hydroxy, methoxy,ethoxy, amino, methylamino, dimethylamino, acetylamino, cyano, halo,methyl, ethyl, trifluoromethyl or trifluoromethoxy; and each Z³¹ isindependently —O—, —NR²¹—, —NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or—S(O)₂—NR²¹—; R⁴ is a radical of hydrogen, C1-C6 alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl, heteroaryl-C₁-C₄ alkyl or R²⁰—Z²⁰—C₂-C₄alkyl radical; and wherein R²⁰ is a hydrogen, C1-C₄ alkyl, aryl,heteroaryl, aryl-C₁-C₂ alkyl or heteroaryl-C₁-C₂ alkyl radical; whereinthe aryl and heteroaryl radicals of R⁴ and R²⁰ are optionallysubstituted by 1-2 radicals of hydroxy, methoxy, ethoxy, methylthiol,ethylthiol, amino, methylamino, dimethylamino, ethylamino, diethylamino,acetylamino, halo, methyl, ethyl, trifluoromethyl or trifluoromethoxy;and R⁵ and R⁶ are each independently a hydrogen, methyl, ethyl, halo,trifluoromethyl, trifluoromethoxy, amino, C₁-C₂ alkylamino, di(C₁-C₂alkyl)amino, hydroxy, methoxy or ethoxy radical; and R⁷ is a hydrogen,methyl, ethyl, halo, trifluoromethyl, trifluoromethoxy, hydroxy, methoxyor ethoxy radical; and wherein cycloalkyl is a monocyclic or bicycliccarbocyclic alkyl radical of 5-10 ring members, which is optionallypartially unsaturated with one double bond, benzo fused or heterocyclofused; aryl is a phenyl or biphenyl radical which is optionally benzofused or heterocyclo fused; heterocyclyl is a radical of a monocyclic orbicyclic saturated heterocyclic ring system having 5-8 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally partially unsaturated or benzo-fusedand optionally substituted by 1-2 oxo or thioxo radicals; and heteroarylis a monocyclic aromatic heterocyclic ring system having 5-6 ringmembers per ring, wherein 1-3 ring members are oxygen, sulfur ornitrogen heteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-carbocyclic-fused.
 12. The compound of claim 11 or apharmaceutically acceptable salt thereof, wherein R¹ is a radical of theformula

wherein R²², R^(23 , R) ²⁴, R²⁵ and R²⁶ are each independently a radicalof hydrogen, C₁-C₄ alkyl, halo, trifluoromethyl, cyano, azido, nitro,amidino, R¹⁸—Z¹⁸— or R¹⁸—Z¹⁸—C₁-C₄ alkyl; provided at least one of R²¹,R²²,R²³, R²⁴ and R²⁵ is hydrogen; and provided that the combined totalnumber of aryl and heteroaryl radicals in R²², R²³, R²⁴, R²⁵ and R²⁶ is0-1; each Z¹⁸ is independently —O—, —S—, —S(O)₂—, —CO₂—, —NR²¹—,—NR²¹—C(O)—, —C(O)—NR²¹—, —NR²¹—S(O)₂— or —S(O)₂—NR²¹—; and wherein arylis a phenyl or biphenyl radical which is optionally benzo fused orheterocyclo fused; and heteroaryl is a monocyclic aromatic heterocyclicring system having 5-6 ring members per ring, wherein 1-3 ring membersare oxygen, sulfur or nitrogen heteroatoms, which is optionallybenzo-fused or saturated C₃-C₄-carbocyclic-fused.
 13. The compound ofclaim 12 or a pharmaceutically acceptable salt thereof, wherein X isNR²; R² is a hydrogen or methyl radical; R⁴ is a radical of hydrogen,methyl or ethyl radical; and R⁵, R⁶ and R⁷ are each independently ahydrogen radical; and wherein aryl is a phenyl, biphenyl or naphthylradical; and heteroaryl is a monocyclic aromatic heterocyclic ringsystem having 5-6 ring members per ring, wherein 1-3 ring members areoxygen, sulfur or nitrogen heteroatoms.
 14. The compound of claim 13 ora pharmaceutically acceptable salt thereof, wherein R¹¹ and R¹³ are eachindependently a radical of hydrogen, methyl, ethyl, fluoro, chloro,trifluoromethyl, cyano, azido, nitro, amidino, R¹⁹—O—, R¹⁹—S(O)₂—,R¹⁹—O—C(O)—, R¹⁹—C(O)—, R¹⁹—NR²¹—C(O)— or R¹⁹—NR²¹—S(O)₂—; provided whenU is C—R¹³ and V and W are each C—R¹², R¹¹ and R¹³ are each other than anitro, cyano, carboxy or alkoxycarbonyl radical; and provided that thecombined total number of aryl and heteroaryl radicals in R¹¹ and R¹³ is0-1; each R¹² is independently a radical of hydrogen, methyl, ethyl,fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy,amino, methylamino, dimethylamino, acetylamino, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, aminomethyl,(methylamino)methyl or (dimethylamino)methyl; and wherein each R¹⁹ isindependently a hydrogen, methyl, ethyl, trifluoromethyl, phenyl,heteroaryl, phenylmethyl or heteroaryl-methyl radical; wherein thephenyl and heteroaryl radicals are optionally substituted by 1-2radicals of hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino,acetylamino, cyano, fluoro, chloro, methyl, ethyl, trifluoromethyl ortrifluoromethoxy.
 15. A pharmaceutical composition comprising a compoundof claim 1 and a pharmaceutically acceptable carrier.
 16. A method forprophylaxis or treatment of inflammation comprising administering aneffective amount of a compound of claim
 1. 17. A method for prophylaxisor treatment of inflammation comprising administering an effectiveamount of a composition of claim 15.